Tricyclic δ-opioid modulators

ABSTRACT

The invention is directed to delta opioid receptor modulators. More specifically, the invention relates to tricyclic δ-opioid modulators. Pharmaceutical and veterinary compositions and methods of treating mild to severe pain and various diseases using compounds of the invention are also described.

CROSS REFERENCE TO RELATED APPLICATIONS

This Application is a divisional of application Ser. No. 13/157,846,filed Jun. 10, 2011 now U.S. Pat. No. 8,106,207, which is a divisionalof application Ser. No. 12/536,635, filed Aug. 6, 2009 now U.S. Pat. No.7,982,042, which is a divisional of application Ser. No. 10/873,527filed Jun. 22, 2004, which issued as U.S. Pat. No. 7,589,103, which inturn claims priority to U.S. Provisional Patent Application No.60/483,389, filed Jun. 27, 2003, now abandoned, which are herebyincorporated by reference in their entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

The research and development of the invention described below was notfederally sponsored.

BACKGROUND OF THE INVENTION

The term “opioid” generically refers to all drugs, natural andsynthetic, that have morphine-like actions. Formerly, the term “opiate”was used to designate drugs derived from opium, e.g., morphine, codeine,and many semi-synthetic congeners of morphine. After the isolation ofpeptide compounds with morphine-like actions, the term opioid wasintroduced to refer generically to all drugs with morphine-like actions.Included among opioids are various peptides that exhibit morphine-likeactivity, such as endorphins, enkephalins and dynorphins. However, somesources have continued to use the term “opiate” in a generic sense, andin such contexts, opiate and opioid are interchangeable. Additionally,the term opioid has been used to refer to antagonists of morphine-likedrugs as well as to characterize receptors or binding sites that combinewith such agents.

Opioids are generally employed as analgesics, but they may have manyother pharmacological effects as well. Morphine and related opioidsproduce their major effects on the central nervous and digestivesystems. The effects are diverse, including analgesia, drowsiness, moodchanges, respiratory depression, dizziness, mental clouding, dysphoria,pruritus, increased pressure in the biliary tract, decreasedgastrointestinal motility, nausea, vomiting, and alterations of theendocrine and autonomic nervous systems.

A significant feature of the analgesia produced by opioids is that itoccurs without loss of consciousness. When therapeutic doses of morphineare given to patients with pain, they report that the pain is lessintense, less discomforting, or entirely gone. In addition toexperiencing relief of distress, some patients experience euphoria.However, when morphine in a selected pain-relieving dose is given to apain-free individual, the experience is not always pleasant; nausea iscommon, and vomiting may also occur. Drowsiness, inability toconcentrate, difficulty in mentation, apathy, lessened physicalactivity, reduced visual acuity, and lethargy may ensue.

Two distinct classes of opioid molecules can bind opioid receptors: theopioid peptides (e.g., the enkephalins, dynorphins, and endorphins) andthe alkaloid opiates (e.g., morphine, etorphine, diprenorphine andnaloxone). Subsequent to the initial demonstration of opiate bindingsites (Pert, C. B. and Snyder, S. H., Science (1973) 179:1011-1014), thedifferential pharmacological and physiological effects of both opioidpeptide analogues and alkaloid opiates served to delineate multipleopioid receptors. Accordingly, three anatomically and pharmacologicallydistinct opioid receptor types have been described: delta, kappa and mu.Furthermore, each type is believed to have sub-types (Wollemann, M., JNeurochem (1990) 54:1095-1101; Lord, J. A., et al., Nature (1977)267:495-499).

All three of these opioid receptor types appear to share the samefunctional mechanisms at a cellular level. For example, the opioidreceptors cause inhibition of adenylate cyclase, and inhibition ofneurotransmitter release via both potassium channel activation andinhibition of Ca²⁺ channels (Evans, C. J., In: Biological Basis ofSubstance Abuse, S. G. Korenman & J. D. Barchas, eds., Oxford UniversityPress (in press); North, A. R., et al., Proc Natl Acad Sci USA (1990)87:7025-29; Gross, R. A., et al., Proc Natl Acad Sci USA (1990)87:7025-29; Sharma, S. K., et al., Proc Natl Acad Sci USA (1975)72:3092-96). Although the functional mechanisms are the same, thebehavioral manifestations of receptor-selective drugs differ greatly(Gilbert, P. E. & Martin, W. R., J Pharmacol Exp Ther (1976) 198:66-82).Such differences may be attributable in part to the anatomical locationof the different receptors.

Delta receptors have a more discrete distribution within the mammalianCNS than either mu or kappa receptors, with high concentrations in theamygdaloid complex, striatum, substantia nigra, olfactory bulb,olfactory tubercles, hippocampal formation, and the cerebral cortex(Mansour, A., et al., Trends in Neurosci (1988) 11:308-14). The ratcerebellum is remarkably devoid of opioid receptors including deltaopioid receptors.

D. Delorme, E. Roberts and Z. Wei, World Patent WO/28275 (1998)discloses diaryl methylidenylpiperidines that are opioid analgesics, butdoes not disclose or suggest the compounds of the present invention.

L. Hermann, C. Ullmer, E. Bellott and others, U.S. Pat. No. 0,166,672(2003), World Patent WO/035646 (2003), and EP 1321169 (2003) disclose4-(thio- or selenoxanthene-9-ylidene)-piperidines or acridines that are5-HT_(2B) receptor antagonists, but do not disclose compounds of thepresent invention.

C. Kaiser, and others in J. Med. Chem. 1974, Volume 17, pages 57-61disclose some piperidylidene derivatives of thioxanthenes, xanthenes,dibenoxepins and acridans that are neuroleptic agents. These authors,however, do not disclose or suggest either the structure or the activityof the compounds of the present invention.

British Patent GB 1128734 (1966) discloses derivatives of6,11-dihydrodibenzo[b,e]oxepine that are anticholinergic,anti-convulsive, muscle-relaxing, sedating, diuretic, and/orcirculatory-active agents. These, agents, however, differ significantlyfrom the compounds of the present invention both structurally andpharmacologically.

There is a continuing need for new delta-opioid receptor modulators asanalgesics. There is a further need for delta-opioid receptor selectiveagonists as analgesics having reduced side-effects. There is also a needfor delta-opioid receptor antagonists as immunosuppressants,antiinflammatory agents, agents for the treatment of neurological andpsychiatric conditions, medicaments for drug and alcohol abuse, agentsfor treating gastritis and diarrhea, cardiovascular agents and agentsfor the treatment of respiratory diseases, having reduced side-effects.

SUMMARY OF THE INVENTION

The present invention is directed to compositions comprising a compoundof Formula (I):

wherein:

-   -   R₁ and R₂ are substituents independently selected from the group        consisting of hydrogen and C₁₋₈alkanyl;    -   R₃ is selected from the group consisting of hydrogen,        C₁₋₈alkanyl, halo₁₋₃(C₁₋₈)alkanyl, C₂₋₈alkenyl, C₂₋₈alkynyl,        C₃₋₈cycloalkanyl, cycloalkanyl(C₁₋₈)alkanyl,        C₁₋₈alkanyloxy(C₁₋₈)alkanyl, C₁₋₈alkanylthio(C₁₋₈)alkanyl,        hydroxyC₁₋₈alkanyl, C₁₋₈alkanyloxycarbonyl,        halo₁₋₃(C₁₋₈)alkanylcarbonyl, formyl, thioformyl, carbamimidoyl,        phenylimino(C₁₋₈)alkanyl, phenyl(C₁₋₈)alkanyl,        phenyl(C₁₋₈)alkenyl, phenyl(C₁₋₈)alkynyl, naphthyl(C₁₋₈)alkanyl        and heteroaryl(C₁₋₈)alkanyl; wherein phenyl, naphthyl and        heteroaryl are optionally substituted with one to three        substituents independently selected from the group consisting of        C₁₋₆alkanyl, C₂₋₆alkenyl, C₁₋₆alkanyloxy, amino,        C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino, C₁₋₆alkanylcarbonyl,        C₁₋₆alkanylcarbonyloxy, C₁₋₆alkanylcarbonylamino,        C₁₋₆alkanylthio, C₁₋₆alkanylsulfonyl, halogen, hydroxy, cyano,        fluoroalkanyl, thioureido, and fluoroalkanyloxy; alternatively,        when phenyl and heteroaryl are optionally substituted with two        substituents attached to adjacent carbon atoms, the two        substituents can together form a single fused moiety; wherein        the fused moiety is selected from the group consisting of        —(CH₂)₃₋₅— and —O(CH₂)₁₋₃O—;    -   R₄ is one to three substituents independently selected from the        group consisting of hydrogen, C₁₋₆alkanyl, C₂₋₆alkenyl,        C₁₋₆alkanyloxy, amino, C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino,        C₁₋₆alkanylcarbonyl, C₁₋₆alkanylcarbonyloxy,        C₁₋₆alkanyloxycarbonyl, C₁₋₆alkanylaminocarbonyl,        di(C₁₋₆alkanyl)aminocarbonyl, C₁₋₆alkanylcarbonylamino,        C₁₋₆alkanylthio, C₁₋₆alkanylsulfonyl, halogen, hydroxy, cyano,        hydroxycarbonyl, C₆₋₁₀aryl, chromanyl, chromenyl, furanyl,        imidazolyl, indazolyl, indolyl, indolinyl, isoindolinyl,        isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl,        oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl,        pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl,        quinoxalinyl, tetrazolyl, thiazolyl, thiophenyl, fluoroalkanyl        and fluoroalkanyloxy; or optionally, when R₄ is two substituents        attached to adjacent carbon atoms, the two substituents together        form a single fused moiety; wherein the fused moiety is selected        from the group consisting of —(CH₂)₃₋₅— and —O(CH₂)₁₋₃O—;    -   R₅ is one to two substituents independently selected from the        group consisting of hydrogen, C₁₋₆alkanyl, C₂₋₆alkenyl,        C₁₋₆alkanyloxy, amino, C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino,        C₁₋₆alkanylcarbonyl, C₁₋₆alkanylcarbonyloxy,        C₁₋₆alkanyloxycarbonyl, C₁₋₆alkanylaminocarbonyl,        C₁₋₆alkanylcarbonylamino, C₁₋₆alkanylthio, C₁₋₆alkanylsulfonyl,        halogen, hydroxy, cyano, fluoroalkanyl and fluoroalkanyloxy;    -   A is —(CH₂)_(m)—, wherein m is 0, 2 or 3; preferably, m is 2 or        3, and most preferably, m is 2    -   Y is —(CH₂)_(n)X— or —X(CH₂)_(n)—;    -   X is O or S    -   n is 0 or 1;    -   Z is O or S;        and enantiomers, diastereomers, tautomers, solvates, or        pharmaceutically acceptable salts thereof.

Finally, the present invention is directed to veterinary andpharmaceutical compositions containing compounds of Formula (I) whereinthe compositions are used to treat mild to severe pain in warm-bloodedanimals.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the following underlined terms are intended to have thefollowing meanings:

“C_(a-b)” (where a and b are integers) refers to a radical containingfrom a to b carbon atoms inclusive. For example, C₁₋₃ denotes a radicalcontaining 1, 2 or 3 carbon atoms

“Alkyl:” refers to a saturated or unsaturated, branched, straight-chainor cyclic monovalent hydrocarbon radical derived by the removal of onehydrogen atom from a single carbon atom of a parent alkane, alkene oralkyne. Typical alkyl groups include, but are not limited to, methyl;ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-1-yl,propan-2-yl, cyclopropan-1-yl ( ), prop-1-en-1-yl, prop-1-en-2-yl,prop-2-en-1-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl,prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butyls such as butan-1-yl,butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl,but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl,but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like. Wherespecific levels of saturation are intended, the nomenclature “alkanyl”,“alkenyl” and/or “alkynyl” is used, as defined below. In preferredembodiments, the alkyl groups are (C₁-C₆) alkyl, with (C₁-C₃) beingparticularly preferred.

“Alkanyl:” refers to a saturated branched, straight-chain or cyclicmonovalent hydrocarbon radical derived by the removal of one hydrogenatom from a single carbon atom of a parent alkane. Typical alkanylgroups include, but are not limited to, methanyl; ethanyl; propanylssuch as propan-1-yl, propan-2-yl, cyclopropan-1-yl, etc.; butyanyls suchas butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl,cyclobutan-1-yl, etc.; and the like. In preferred embodiments, thealkanyl groups are (C₁₋₈) alkanyl, with (C₁₋₃) being particularlypreferred.

“Alkenyl” refers to an unsaturated branched, straight-chain or cyclicmonovalent hydrocarbon radical having at least one carbon-carbon doublebond derived by the removal of one hydrogen atom from a single carbonatom of a parent alkene. The radical may be in either the cis or transconformation about the double bond(s). Typical alkenyl groups include,but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl,prop-1-en-2-yl, prop-2-en-1-yl, prop-2-en-2-yl, cycloprop-1-en-1-yl;cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl,2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl,buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl,cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.; and the like.

“Alkenyl” refers to an unsaturated branched, straight-chain or cyclicmonovalent hydrocarbon radical having at least one carbon-carbon triplebond derived by the removal of one hydrogen atom from a single carbonatom of a parent alkyne. Typical alkynyl groups include, but are notlimited to, ethynyl; propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl,etc.; butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl,etc.; and the like.

“Heteroalkyl” and Heteroalkanyl” refer to alkyl or alkanyl radicals,respectively, in which one or more carbon atoms (and any necessaryassociated hydrogen atoms) are independently replaced with the same ordifferent heteroatoms (including any necessary hydrogen or other atoms).Typical heteroatoms to replace the carbon atom(s) include, but are notlimited to, N, P, O, S, Si, etc. Preferred heteroatoms are O, N and S.Thus, heteroalkanyl radicals can contain one or more of the same ordifferent heteroatomic groups, including, by way of example and notlimitation, epoxy (—O—), epidioxy (—O—O—), thioether (—S—), epidithio(—SS—), epoxythio (—O—S—), epoxyimino (—O—NR′—), imino (—NR′—), biimino(—NR′—NR′—), azino (═N—N═), azo (—N═N—), azoxy (—N—O—N—), azimino(—NR′—N═N—), phosphano (—PH—), λ⁴-sulfano (—SH₂—), sulfonyl (—S(O)₂—),and the like, where each R′ is independently hydrogen or (C₁-C₆) alkyl.

“Parent Aromatic Ring System:” refers to an unsaturated cyclic orpolycyclic ring system having a conjugated π electron system.Specifically included within the definition of “parent aromatic ringsystem” are fused ring systems in which one or more rings are aromaticand one or more rings are saturated or unsaturated, such as, forexample, indane, indene, phenalene, etc. Typical parent aromatic ringsystems include, but are not limited to, aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexylene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, trinaphthalene, and the like

“Aryl:” refers to a monovalent aromatic hydrocarbon radical derived bythe removal of one hydrogen atom from a single carbon atom of a parentaromatic ring system. Typical aryl groups include, but are not limitedto, radicals derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexylene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, trinaphthalene, and the like. In preferredembodiments, the aryl group is (C₅₋₂₀) aryl, with (C₅₋₁₀) beingparticularly preferred. Particularly preferred aryl groups are phenyland naphthyl groups.

“Arylalkyl:” refers to an acyclic alkyl group in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal carbonatom, is replaced with an aryl radical. Typical arylalkyl groupsinclude, but are not limited to, benzyl, 2-phenylethan-1-yl,2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl,2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and thelike. Where specific alkyl moieties are intended, the nomenclaturearylalkanyl, arylakenyl and/or arylalkynyl is used. [In preferredembodiments, the arylalkyl group is (C₆₋₂₆) arylalkyl, e.g., thealkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C₁₋₆) andthe aryl moiety is (C₅₋₂₀). In particularly preferred embodiments thearylalkyl group is (C₆₋₁₃), e.g., the alkanyl, alkenyl or alkynyl moietyof the arylalkyl group is (C₁₋₃) and the aryl moiety is (C₅₋₁₀). Evenmore preferred arylalkyl groups are phenylalkanyls.

“Alkanyloxy:” refers to a saturated branched, straight-chain or cyclicmonovalent hydrocarbon alcohol radical derived by the removal of thehydrogen atom from the hydroxide oxygen of the alcohol. Typicalalkanyloxy groups include, but are not limited to, methanyloxy;ethanyloxy; propanyloxy groups such as propan-1-yloxy (CH₃CH₂CH₂O—),propan-2-yloxy ((CH₃)₂CHO—), cyclopropan-1-yloxy, etc.; butanyloxygroups such as butan-1-yloxy, butan-2-yloxy, 2-methyl-propan-1-yloxy,2-methyl-propan-2-yloxy, cyclobutan-1-yloxy, etc.; and the like. Inpreferred embodiments, the alkanyloxy groups are (C₁₋₈) alkanyloxygroups, with (C₁₋₃) being particularly preferred.

“Parent Heteroaromatic Ring System:” refers to a parent aromatic ringsystem in which one carbon atom is replaced with a heteroatom.Heteratoms to replace the carbon atoms include N, O, and S. Specificallyincluded within the definition of “parent heteroaromatic ring systems”are fused ring systems in which one or more rings are aromatic and oneor more rings are saturated or unsaturated, such as, for example,arsindole, chromane, chromene, indole, indoline, xanthene, etc. Typicalparent heteroaromatic ring systems include, but are not limited to,carbazole, imidazole, indazole, indole, indoline, indolizine, isoindole,isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine,oxadiazole, oxazole, purine, pyran, pyrazine, pyrazole, pyridazine,pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline,quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene,triazole, xanthene, and the like.

“Heteroaryl:” refers to a monovalent heteroaromatic radical derived bythe removal of one hydrogen atom from a single atom of a parentheteroaromatic ring system. Typical heteroaryl groups include, but arenot limited to, radicals derived from carbazole, imidazole, indazole,indole, indoline, indolizine, isoindole, isoindoline, isoquinoline,isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, purine,pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole,pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and thelike. In preferred embodiments, the heteroaryl group is a 5-20 memberedheteroaryl, with 5-10 membered heteroaryl being particularly preferred.

“Cycloheteroalkyl:” refers to a saturated or unsaturated monocyclic orbicyclic alkyl radical in which one carbon atom is replaced with N, O orS. In certain specified embodiments the cycloheteroalkyl may contain upto four heteroatoms independently selected from N, O or S. Typicalcycloheteroalkyl moieties include, but are not limited to, radicalsderived from imidazolidine, morpholine, piperazine, piperidine,pyrazolidine, pyrrolidine, quinuclidine, and the like. In preferredembodiments, the cycloheteroalkyl is a 3-6 membered cycloheteroalkyl.

“Cycloheteroalkanyl:” refers to a saturated monocyclic or bicyclicalkanyl radical in which one carbon atom is replaced with N, O or S. Incertain specified embodiments the cycloheteroalkanyl may contain up tofour heteroatoms independently selected from N, O or S. Typicalcycloheteroalkanyl moieties include, but are not limited to, radicalsderived from imidazolidine, morpholine, piperazine, piperidine,pyrazolidine, pyrrolidine, quinuclidine, and the like. In preferredembodiments, the cycloheteroalkanyl is a 3-6 memberedcycloheteroalkanyl.

“Cycloheteroalkenyl:” refers to a saturated monocyclic or bicyclicalkenyl radical in which one carbon atom is replaced with N, O or S. Incertain specified embodiments the cycloheteroalkenyl may contain up tofour heteroatoms independently selected from N, O or S. Typicalcycloheteroalkenyl moieties include, but are not limited to, radicalsderived from imidazoline, pyrazoline, pyrroline, indoline, pyran, andthe like. In preferred embodiments, the cycloheteroalkanyl is a 3-6membered cycloheteroalkanyl.

“Substituted:” refers to a radical in which one or more hydrogen atomsare each independently replaced with the same or differentsubstituent(s). Typical substituents include, but are not limited to,—X, —R, —O⁻, ═O, —OR, —O—OR, —SR, —S⁻, ═S, —NRR, ═NR, —CX₃, —CN, —OCN,—SCN, —NCO, —NCS, —NO, —NO₂, ═N₂, —N₃, —NHOH, —S(O)₂O⁻, —S(O)₂OH,—S(O)₂R, —P(O)(O⁻)₂, —P(O)(OH)₂, —C(O)R, —C(O)X, —C(S)R, —C(S)X,—C(O)OR, —C(O)O⁻, —C(S)OR, —C(O)SR, —C(S)SR, —C(O)NRR, —C(S)NRR and—C(NR)NRR, where each X is independently a halogen (preferably —F, —Clor —Br) and each R is independently —H, alkyl, alkanyl, alkenyl,alkynyl, alkylidene, alkylidyne, aryl, arylalkyl, arylheteroalkyl,heteroaryl, heteroarylalkyl or heteroaryl-heteroalkyl, as definedherein. Preferred substituents include hydroxy, halogen, C₁₋₈alkyl,C₁₋₈alkanyloxy, fluorinated alkanyloxy, fluorinated alkyl,C₁₋₈alkylthio, C₃₋₈cycloalkyl, C₃₋₈cycloalkanyloxy, nitro, amino,C₁₋₈alkylamino, C₁₋₈dialkylamino, C₃₋₈cycloalkylamino, cyano, carboxy,C₁₋₇alkanyloxycarbonyl, C₁₋₇alkylcarbonyloxy, formyl, carbamoyl, phenyl,aroyl, carbamoyl, amidino, (C₁₋₈alkylamino)carbonyl, (arylamino)carbonyland aryl(C₁₋₈alkyl)carbonyl.

With reference to substituents, the term “independently” means that whenmore than one of such substituent is possible, such substituents may bethe same or different from each other.

Throughout this disclosure, the terminal portion of the designated sidechain is described first, followed by the adjacent functionality towardthe point of attachment. Thus, for example, a“phenylC₁₋₆alkanylaminocarbonylC₁₋₆alkyl” substituent refers to a groupof the formula

An embodiment of the present invention is directed to a compound ofFormula (I) wherein the structure is numbered as defined herein.

The present invention is directed to analgesic and anti-pyretic uses ofcompositions comprising a compound of Formula (I):

wherein:

-   -   R₁ and R₂ are substituents independently selected from the group        consisting of hydrogen and C₁₋₈alkanyl;    -   R₃ is selected from the group consisting of hydrogen,        C₁₋₈alkanyl, halo₁₋₃(C₁₋₈)alkanyl, C₂₋₈alkenyl, C₂₋₈alkynyl,        C₃₋₈cycloalkanyl, cycloalkanyl(C₁₋₈)alkanyl,        C₁₋₈alkanyloxy(C₁₋₈)alkanyl, C₁₋₈alkanylthio(C₁₋₈)alkanyl,        hydroxyC₁₋₈alkanyl, C₁₋₈alkanyloxycarbonyl,        halo₁₋₃(C₁₋₈)alkanylcarbonyl, formyl, thioformyl, carbamimidoyl,        phenylimino(C₁₋₈)alkanyl, phenyl(C₁₋₈)alkanyl,        phenyl(C₁₋₈)alkenyl, phenyl(C₁₋₈)alkynyl, naphthyl(C₁₋₈)alkanyl        and heteroaryl(C₁₋₈)alkanyl; wherein phenyl, naphthyl and        heteroaryl are optionally substituted with one to three        substituents independently selected from the group consisting of        C₁₋₆alkanyl, C₂₋₆alkenyl, C₁₋₆alkanyloxy, amino,        C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino, C₁₋₆alkanylcarbonyl,        C₁₋₆alkanylcarbonyloxy, C₁₋₆alkanylcarbonylamino,        C₁₋₆alkanylthio, C₁₋₆alkanylsulfonyl, halogen, hydroxy, cyano,        fluoroalkanyl, thioureido, and fluoroalkanyloxy; or optionally,        when phenyl and heteroaryl are optionally substituted with two        substituents attached to adjacent carbon atoms, the two        substituents together form a single fused moiety; wherein the        fused moiety is selected from the group consisting of —(CH₂)₃₋₅—        and —O(CH₂)₁₋₃O—;    -   R₄ is one to three substituents independently selected from the        group consisting of hydrogen, C₁₋₆alkanyl, C₂₋₆alkenyl,        C₁₋₆alkanyloxy, amino, C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino,        C₁₋₆alkanylcarbonyl, C₁₋₆alkanylcarbonyloxy,        C₁₋₆alkanyloxycarbonyl, C₁₋₆alkanylaminocarbonyl,        di(C₁₋₆alkanyl)aminocarbonyl, C₁₋₆alkanylcarbonylamino,        C₁₋₆alkanylthio, C₁₋₆alkanylsulfonyl, halogen, hydroxy, cyano,        hydroxycarbonyl, C₆₋₁₀aryl, chromanyl, chromenyl, furanyl,        imidazolyl, indazolyl, indolyl, indolinyl, isoindolinyl,        isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl,        oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl,        pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl,        quinoxalinyl, tetrazolyl, thiazolyl, thiophenyl, fluoroalkanyl        and fluoroalkanyloxy; or optionally, when R₄ is two substituents        attached to adjacent carbon atoms, the two substituents together        form a single fused moiety; wherein the fused moiety is selected        from the group consisting of —(CH₂)₃₋₅— and —O(CH₂)₁₋₃O—;    -   R₅ is one to two substituents independently selected from the        group consisting of hydrogen, C₁₋₆alkanyl, C₂₋₆alkenyl,        C₁₋₆alkanyloxy, amino, C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino,        C₁₋₆alkanylcarbonyl, C₁₋₆alkanylcarbonyloxy,        C₁₋₆alkanyloxycarbonyl, C₁₋₆alkanylaminocarbonyl,        C₁₋₆alkanylcarbonylamino, C₁₋₆alkanylthio, C₁₋₆alkanylsulfonyl,        halogen, hydroxy, cyano, fluoroalkanyl and fluoroalkanyloxy;    -   A is —(CH₂)_(m)—, wherein m is 0, 2 or 3;    -   Y is —(CH₂)_(n)X— or —X(CH₂)_(n)—;    -   X is O or S;    -   n is 0 or 1;    -   Z is O or S;

-   and enantiomers, diastereomers, tautomers, solvates, and    pharmaceutically acceptable salts thereof.

For embodiments of the present invention, preferably:

-   a) R₁ and R₂ are substituents independently selected from the group    consisting of hydrogen and C₁₋₄alkanyl;-   b) R₁ and R₂ are substituents independently selected from the group    consisting of hydrogen, methyl, ethyl and propyl;-   c) R₁ and R₂ are substituents independently selected from the group    consisting of hydrogen and ethyl;-   d) R₃ is selected from the group consisting of hydrogen,    C₁₋₈alkanyl, C₂₋₈alkenyl, C₂₋₈alkynyl, C₁₋₈alkanyloxy(C₁₋₈)alkanyl,    C₁₋₈alkanylthio(C₁₋₈)alkanyl, hydroxyC₁₋₈alkanyl, thioformyl,    phenylimino(C₁₋₈)alkanyl, phenyl(C₁₋₈)alkanyl, and    heteroaryl(C₁₋₈)alkanyl; wherein phenyl and heteroaryl are    optionally substituted with one to three substituents independently    selected from the group consisting of C₁₋₆alkanyloxy and hydroxy; or    optionally, when phenyl and heteroaryl are optionally substituted    with two substituents attached to adjacent carbon atoms, the two    substituents together form a single fused moiety; wherein the moiety    is selected from —O(CH₂)₁₋₃O—;-   e) R₃ is selected from the group consisting of hydrogen, methyl,    allyl, 2-methyl-allyl, propynyl, hydroxyethyl, methylthioethyl,    methoxyethyl, thioformyl, phenyliminomethyl, phenethyl, and    heteroaryl(C₁₋₈)alkanyl; wherein the phenyl in any phenyl-containing    substituent is optionally substituted with one hydroxyl group;-   f) R₃ is hydrogen, methyl, allyl, or heteroarylmethyl;-   g) R₄ is one to three substituents independently selected from the    group consisting of hydrogen, C₁₋₆alkanyl, C₁₋₆alkanyloxy,    C₁₋₆alkanylaminocarbonyl, C₁₋₆alkanylcarbonylamino, halogen,    hydroxy, C₆₋₁₀aryl, chromanyl, chromenyl, furanyl, imidazolyl,    indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl,    isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl, pyrazinyl,    pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl,    quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrazolyl,    thiazolyl, and thiophenyl;-   h) R₄ is one to two substituents independently selected from the    group consisting of hydrogen, C₁₋₄alkanyl, C₁₋₄alkanyloxy, halogen,    phenyl, furanyl, imidazolyl, indazolyl, indolyl, indolinyl,    isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl,    pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl,    quinolinyl, tetrazolyl, thiazolyl, thiophenyl, and hydroxy;-   i) R₄ is one to two substituents independently selected from the    group consisting of hydrogen, methyl, methoxy, bromo, fluoro, 5- or    6-phenyl, 5- or 6-pyridinyl, 5- or 6-furanyl, and hydroxy;-   j) R₅ is one to two substituents independently selected from the    group consisting of hydrogen and halogen;-   k) R₅ is hydrogen;-   l) A is —(CH₂)₀₋₂—;-   m) A is —(CH₂)₂—;-   n) X is O or S;-   o) n is 0;-   p) Z is O; and-   q) combinations of a) through p) above.

One embodiment of the present invention is a compound of Formula (I)

wherein:

-   -   R₁ is C₁₋₃alkanyl;    -   R₂ is C₁₋₃alkanyl or hydrogen;    -   R₃ is selected from the group consisting of hydrogen,        C₁₋₈alkanyl, C₂₋₈alkenyl, C₂₋₈alkynyl,        C₁₋₈alkanyloxy(C₁₋₈)alkanyl, C₁₋₈alkanylthio(C₁₋₈)alkanyl,        hydroxyC₁₋₈alkanyl, thioformyl, phenylimino(C₁₋₈)alkanyl,        phenyl(C₁₋₈)alkanyl, and heteroaryl(C₁₋₈)alkanyl; wherein phenyl        and heteroaryl are optionally substituted with one to three        substituents independently selected from the group consisting of        C₁₋₆alkanyloxy and hydroxy; or optionally, when phenyl and        heteroaryl are optionally substituted with two substituents        attached to adjacent carbon atoms, the two substituents together        form a single fused moiety; wherein the moiety is selected from        —O(CH₂)₁₋₃O—;    -   R₄ is one to three substituents independently selected from the        group consisting of hydrogen, C₁₋₆alkanyl, C₁₋₆alkanyloxy,        C₁₋₆alkanylaminocarbonyl, C₁₋₆alkanylcarbonylamino, halogen,        hydroxy, C₆₋₁₀aryl, chromanyl, chromenyl, furanyl, imidazolyl,        indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl,        isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl, pyrazinyl,        pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl,        quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl,        tetrazolyl, thiazolyl, and thiophenyl;    -   R₅ is one to two substituents independently selected from the        group consisting of hydrogen and halogen;    -   A is absent or CH₂CH₂;    -   Y is O, S, CH₂O or OCH₂;    -   Z is O; and        enantiomers, diastereomers, tautomers, solvates, and        pharmaceutically acceptable salts thereof.

Another embodiment of the present invention is a compound of Formula (I)wherein:

-   -   R₁ is C₁₋₃alkanyl;    -   R₂ is C₁₋₃alkanyl or hydrogen;    -   R₃ is selected from the group consisting of hydrogen, methyl,        allyl, 2-methyl-allyl, propynyl, hydroxyethyl, methoxyethyl,        methylthioethyl, thioformyl, phenyliminomethyl, phenethyl, and        heteroaryl(C₁₋₈)alkanyl; wherein the phenyl in any        phenyl-containing substituent is optionally substituted with one        hydroxyl group;    -   R₄ is one to two substituents independently selected from the        group consisting of hydrogen, C₁₋₄alkanyl, C₁₋₄alkanyloxy,        halogen, phenyl, furanyl, imidazolyl, indazolyl, indolyl,        indolinyl, isoindolinyl, isoquinolinyl, isothiazolyl,        isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,        pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl,        thiazolyl, thiophenyl, and hydroxy;    -   R₅ is hydrogen;    -   A is absent or CH₂CH₂;    -   Y is O, S, CH₂O or OCH₂;    -   Z is O; and    -   enantiomers, diastereomers, tautomers, solvates, and        pharmaceutically acceptable salts thereof.

Another embodiment of the present invention is directed to compositionscomprising a compound of Formula (I) wherein R₁ is ethyl; R₂ is ethyl orhydrogen; R₃ is a substituent selected from the group consisting ofbenzo[1,3]dioxol-5-ylmethyl, carbamimidoyl, 1-H-imidazol-4-ylmethyl,phenyliminomethyl, 1-prop-2-ynyl, thioformyl, 2-hydroxyphenyl-methyl,hydroxy-ethyl, methoxy-ethyl, 2-methyl-allyl, 2-methyl-but-2-enyl,allyl, furan-3-ylmethyl, H, Me, methylthioethyl, phenethyl, pyridin-2-ylmethyl, thiophen-2-yl methyl; R₄ is one to two substituentsindependently selected from the group consisting of hydrogen,C₁₋₄alkanyl, C₁₋₄alkanyloxy, halogen, phenyl, furanyl, imidazolyl,indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl,isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl,thiophenyl, and hydroxy; A is absent or CH₂CH₂; Y is O or S; and Z is O.

Another embodiment of the present invention is a compound of Formula (I)wherein:

-   -   R₁ is C₁₋₃alkanyl;    -   R₂ is C₁₋₃alkanyl or hydrogen;    -   R₃ is selected from the group consisting of hydrogen,        C₁₋₈alkanyl, C₂₋₈alkenyl, C₂₋₈alkynyl,        C₁₋₈alkanyloxy(C₁₋₈)alkanyl, C₁₋₈alkanylthio(C₁₋₈)alkanyl,        hydroxyC₁₋₈alkanyl, thioformyl, phenylimino(C₁₋₈)alkanyl,        phenyl(C₁₋₈)alkanyl, and heteroaryl(C₁₋₈)alkanyl; wherein phenyl        and heteroaryl are optionally substituted with one to three        substituents independently selected from the group consisting of        C₁₋₆alkanyloxy and hydroxy; or optionally, when phenyl and        heteroaryl are optionally substituted with two substituents        attached to adjacent carbon atoms, the two substituents together        form a single fused moiety; wherein the moiety is selected from        —O(CH₂)₁₋₃O—;    -   R₄ is one to three substituents independently selected from the        group consisting of hydrogen, C₁₋₆alkanyl, C₁₋₆alkanyloxy,        C₁₋₆alkanylaminocarbonyl, C₁₋₆alkanylcarbonylamino, halogen,        hydroxy, C₆₋₁₀aryl, chromanyl, chromenyl, furanyl, imidazolyl,        indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl,        isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl, pyrazinyl,        pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl,        quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl,        tetrazolyl, thiazolyl, and thiophenyl;    -   R₅ is one to two substituents independently selected from the        group consisting of hydrogen and halogen;    -   A CH₂CH₂;    -   Y is O, S, CH₂O or OCH₂;    -   Z is O; and        enantiomers, diastereomers, tautomers, solvates, and        pharmaceutically acceptable salts thereof.

Another embodiment of the present invention is a compound of Formula (I)wherein:

-   -   R₁ is C₁₋₃alkanyl;    -   R₂ is C₁₋₃alkanyl or hydrogen;    -   R₃ is selected from the group consisting of hydrogen, methyl,        allyl, 2-methyl-allyl, propynyl, hydroxyethyl, methoxyethyl,        methylthioethyl, thioformyl, phenyliminomethyl, phenethyl, and        heteroaryl(C₁₋₈)alkanyl; wherein the phenyl in any        phenyl-containing substituent is optionally substituted with one        hydroxyl group;    -   R₄ is one to two substituents independently selected from the        group consisting of hydrogen, C₁₋₄alkanyl, C₁₋₄alkanyloxy,        halogen, phenyl, furanyl, imidazolyl, indazolyl, indolyl,        indolinyl, isoindolinyl, isoquinolinyl, isothiazolyl,        isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,        pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl,        thiazolyl, thiophenyl, and hydroxy;    -   R₅ is hydrogen;    -   A is CH₂CH₂;    -   Y is O, S, CH₂O or OCH₂;    -   Z is O; and    -   enantiomers, diastereomers, tautomers, solvates, and        pharmaceutically acceptable salts thereof.

Another embodiment of the present invention is directed to compositionscomprising a compound of Formula (I) wherein R₁ is ethyl; R₂ is ethyl orhydrogen; R₃ is a substituent selected from the group consisting ofbenzo[1,3]dioxol-5-ylmethyl, carbamimidoyl, 1-H-imidazol-4-ylmethyl,phenyliminomethyl, 1-prop-2-ynyl, thioformyl, 2-hydroxyphenyl-methyl,hydroxy-ethyl, methoxy-ethyl, 2-methyl-allyl, 2-methyl-but-2-enyl,allyl, furan-3-ylmethyl, H, Me, methylthioethyl, phenethyl, pyridin-2-ylmethyl, thiophen-2-yl methyl; R₄ is one to two substituentsindependently selected from the group consisting of hydrogen,C₁₋₄alkanyl, C₁₋₄alkanyloxy, halogen, phenyl, furanyl, imidazolyl,indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl,isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl,thiophenyl, and hydroxy; A is CH₂CH₂; Y is O or S; and Z is O.

Another embodiment of the present invention is directed to compositionscomprising a compound of Formula (I) wherein R₁ is ethyl; R₂ is ethyl;R₃ is a substituent selected from the group consisting ofbenzo[1,3]dioxol-5-ylmethyl, carbamimidoyl, 1-H-imidazol-4-yl methyl,phenyliminomethyl, 1-prop-2-ynyl, thioformyl, 2-hydroxyphenyl-methyl,hydroxyethyl, methoxyethyl, allyl, furan-3-yl methyl, H, Me,methylthioethyl, and phenethyl; R₄ is one to two substituentsindependently selected from the group consisting of hydrogen, methyl,methoxy, bromo, fluoro, 5- or 6-phenyl, 5- or 6-pyridinyl, 5- or6-furanyl, and hydroxy; A is CH₂CH₂; Y is O or S; and Z is O.

Another embodiment of the present invention is directed to compositionscomprising a compound of Formula (I) wherein R₁ is ethyl; R₂ is ethyl;R₃ is a substituent selected from the group consisting of H,benzo[1,3]dioxol-5-ylmethyl, 1-H-imidazol-4-yl methyl, furan-3-ylmethyl,pyridin-2-ylmethyl, and phenyliminomethyl; R₄ is a substituentindependently selected from the group consisting of hydrogen, methyl,methoxy, bromo, fluoro, 5- or 6-phenyl, 5- or 6-pyridinyl, 5- or6-furanyl, and hydroxy; A is CH₂CH₂; Y is O or S; and Z is O.

Another embodiment of the present invention is directed to a compound ofFormula (I) wherein R₄ is preferably substituted at the 5- or 6-positionof Formula (I).

Another embodiment of the present invention is directed to compositionscomprising a compound selected from the group consisting of:

-   -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is methyl, R₄ is H, R₅ is H, A is absent, Y is CH₂O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is H, R₅ is H, A is absent, Y is CH₂O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is H, R₅ is H, A is absent, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is benzo[1,3]dioxol-5-ylmethyl, R₄ is H, R₅ is H, A is absent, Y        is CH₂O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is phenethyl, R₄ is H, R₅ is H, A is absent, Y is CH₂O, and Z is        O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is allyl, R₄ is H, R₅ is H, A is absent, Y is CH₂O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is methyl, R₄ is H, R₅ is H, A is absent, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is allyl, R₄ is H, R₅ is H, A is absent, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is H, R₃ is        methyl, R₄ is H, R₅ is H, A is absent, Y is CH₂O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is H, R₃ is        1,1,1-trichloroethoxycarbonyl, R₄ is H, R₅ is H, A is absent, Y        is CH₂O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is H, R₃ is H,        R₄ is H, R₅ is H, A is absent, Y is CH₂O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is H, R₃ is        2-methyl-but-2-enyl, R₄ is H, R₅ is H, A is absent, Y is CH₂O,        and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is H, R₃ is        thiophen-2-yl methyl, R₄ is H, R₅ is H, A is absent, Y is CH₂O,        and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is H, R₃ is        2-methyl-allyl, R₄ is H, R₅ is H, A is absent, Y is CH₂O, and Z        is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is H, R₃ is        cyclopropylmethyl, R₄ is H, R₅ is H, A is absent, Y is CH₂O, and        Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is H, R₃ is        pyridin-2-yl methyl, R₄ is H, R₅ is H, A is absent, Y is CH₂O,        and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is H, R₃ is        1-H-imidazol-4-yl methyl, R₄ is H, R₅ is H, A is absent, Y is        CH₂O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is H, R₃ is        4-hydroxy-3-methoxyphenyl-methyl, R₄ is H, R₅ is H, A is absent,        Y is CH₂O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is H, R₃ is        allyl, R₄ is H, R₅ is H, A is absent, Y is CH₂O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is H, R₃ is        phenethyl, R₄ is H, R₅ is H, A is absent, Y is CH₂O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is phenethyl, R₄ is H, R₅ is H, A is absent, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is methyl, R₄ is H, R₅ is H, A is CH₂CH₂, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is H, R₅ is H, A is CH₂CH₂, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is furan-3-yl methyl, R₄ is H, R₅ is H, A is CH₂CH₂, Y is O, and        Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is H, R₃ is        phenethyl, R₄ is H, R₅ is H, A is CH₂CH₂, Y is CH₂O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is H, R₃ is        phenethyl, R₄ is H, R₅ is H, A is CH₂CH₂, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is furan-3-yl methyl, R₄ is H, R₅ is H, A is absent, Y is O, and        Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is pyridin-2-yl methyl, R₄ is H, R₅ is H, A is absent, Y is O,        and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is 2-hydroxyphenyl-methyl, R₄ is H, R₅ is H, A is absent, Y is        O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is carbamimidoyl, R₄ is H, R₅ is H, A is absent, Y is O, and Z        is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is H, R₃ is H,        R₄ is H, R₅ is H, A is absent, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is 1-prop-2-ynyl, R₄ is H, R₅ is H, A is absent, Y is O, and Z        is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is methylcarbonylamino, R₅ is H, A is absent, Y is O,        and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is hydroxy-ethyl, R₄ is H, R₅ is H, A is absent, Y is O, and Z        is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is phenyliminomethyl, R₄ is H, R₅ is H, A is absent, Y is O, and        Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is thioformyl, R₄ is H, R₅ is H, A is absent, Y is O, and Z is        O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is allyl, R₄ is H, R₅ is H, A is CH₂CH₂, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is methoxyethyl, R₄ is H, R₅ is H, A is CH₂CH₂, Y is O, and Z is        O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is methylthio-ethyl, R₄ is H, R₅ is H, A is CH₂CH₂, Y is O, and        Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is methyl, R₄ is methylcarbonylamino, R₅ is H, A is absent, Y is        O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is H, R₅ is H, A is absent, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is methyl, R₄ is H, R₅ is H, A is absent, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is pyridin-2-yl methyl, R₄ is H, R₅ is H, A is CH₂CH₂, Y is O,        and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is hydroxyethyl, R₄ is H, R₅ is H, A is CH₂CH₂, Y is O, and Z is        O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is 1-H-imidazol-4-yl methyl, R₄ is H, R₅ is H, A is CH₂CH₂, Y is        O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is benzo[1,3]dioxol-5-ylmethyl, R₄ is H, R₅ is H, A is CH₂CH₂, Y        is S, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is H, R₅ is H, A is CH₂CH₂, Y is S, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is cyclopropylmethyl, R₄ is H, R₅ is H, A is CH₂CH₂, Y is S, and        Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is methylthio-propyl, R₄ is H, R₅ is H, A is CH₂CH₂, Y is S, and        Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is hydroxy-ethyl, R₄ is H, R₅ is H, A is CH₂CH₂, Y is S, and Z        is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is H, R₅ is H, A is CH₂CH₂, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is H, R₅ is H, A is CH₂CH₂, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is H, R₃ is H,        R₄ is H, R₅ is H, A is CH₂CH₂, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is methyl, R₂ is methyl, R₃        is H, R₄ is H, R₅ is H, A is CH₂CH₂, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is isopropyl, R₂ is H, R₃        is H, R₄ is H, R₅ is H, A is CH₂CH₂, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is methyl, R₂ is isobutyl,        R₃ is H, R₄ is H, R₅ is H, A is CH₂CH₂, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is n-propyl, R₂ is        n-propyl, R₃ is H, R₄ is H, R₅ is H, A is CH₂CH₂, Y is O, and Z        is O;    -   a compound of Formula (I) wherein R₁ is n-propyl, R₂ is H, R₃ is        H, R₄ is H, R₅ is H, A is CH₂CH₂, Y is S, and Z is O;    -   a compound of Formula (I) wherein R₁ is methyl, R₂ is H, R₃ is        H, R₄ is H, R₅ is H, A is CH₂CH₂, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is H, R₂ is H, R₃ is H, R₄        is H, R₅ is H, A is CH₂CH₂, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is 6-methyl, R₅ is H, A is CH₂CH₂, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is 7-methyl, R₅ is H, A is CH₂CH₂, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is 5-methoxy, R₅ is H, A is CH₂CH₂, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is 7-fluoro, R₅ is H, A is CH₂CH₂, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is 6-methoxy, R₅ is H, A is CH₂CH₂, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is 1-H-imidazol-5-ylmethyl, R₄ is H, R₅ is H, A is CH₂CH₂, Y is        O, and Z is O;    -   a compound of Formula (I) wherein R₁ is methyl, R₂ is n-butyl,        R₃ is H, R₄ is H, R₅ is H, A is CH₂CH₂, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is 1-H-imidazol-4-ylmethyl, R₄ is H, R₅ is H, A is CH₂CH₂, Y is        S, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is 6-hydroxy, R₅ is H, A is CH₂CH₂, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is 7-methoxy, R₅ is H, A is CH₂CH₂, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is H, R₃ is        trifluoromethylcarbonyl, R₄ is H, R₅ is H, A is CH₂CH₂, Y is S,        and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is H, R₃ is H,        R₄ is H, R₅ is H, A is CH₂CH₂, Y is S, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is 7-hydroxy, R₅ is H, A is CH₂CH₂, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is 7-bromo, R₅ is H, A is CH₂CH₂, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is 7-phenyl, R₅ is H, A is CH₂CH₂, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is 7-pyridin-4-yl, R₅ is H, A is CH₂CH₂, Y is O, and Z        is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is 7-furan-3-yl, R₅ is H, A is CH₂CH₂, Y is O, and Z is        O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is 7-benzothiophen-2-yl, R₅ is H, A is CH₂CH₂, Y is O,        and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is 7-(N-t-butoxycarbonyl)pyrrol-2-yl, R₅ is H, A is        CH₂CH₂, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is 7-pyridin-3-yl, R₅ is H, A is CH₂CH₂, Y is O, and Z        is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is 7-thiophen-3-yl, R₅ is H, A is CH₂CH₂, Y is O, and Z        is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is 7-(3,5-dimethyl)isoxazol-4-yl, R₅ is H, A is CH₂CH₂,        Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is methyl, R₂ is isopropyl,        R₃ is H, R₄ is H, R₅ is H, A is CH₂CH₂, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is 7-pyrrol-2-yl, R₅ is H, A is CH₂CH₂, Y is O, and Z        is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is 5-bromo, R₅ is H, A is CH₂CH₂, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is 5-phenyl, R₅ is H, A is CH₂CH₂, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is 5-pyridin-4-yl, R₅ is H, A is CH₂CH₂, Y is O, and Z        is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is 5-furan-3-yl, R₅ is H, A is CH₂CH₂, Y is O, and Z is        O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is 5-quinolin-3-yl, R₅ is H, A is CH₂CH₂, Y is O, and Z        is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is 5-thiophen-3-yl, R₅ is H, A is CH₂CH₂, Y is O, and Z        is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is 5-hydroxy, R₅ is H, A is CH₂CH₂, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is 5-pyridin-3-yl, R₅ is H, A is CH₂CH₂, Y is O, and Z        is O; and    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is 5-fluoro, R₅ is H, A is CH₂CH₂, Y is O, and Z is O.

Another embodiment of the present invention is directed to compositionscomprising a compound selected from the group consisting of:

-   -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is H, R₃ is H,        R₄ is H, R₅ is H, A is absent, Y is CH₂O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is H, R₃ is        2-methyl-but-2-enyl, R₄ is H, R₅ is H, A is absent, Y is CH₂O,        and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is H, R₃ is        thiophen-2-yl methyl, R₄ is H, R₅ is H, A is absent, Y is CH₂O,        and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is H, R₃ is        2-methyl-allyl, R₄ is H, R₅ is H, A is absent, Y is CH₂O, and Z        is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is H, R₃ is        pyridin-2-yl methyl, R₄ is H, R₅ is H, A is absent, Y is CH₂O,        and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is H, R₃ is        1-H-imidazol-4-yl methyl, R₄ is H, R₅ is H, A is absent, Y is        CH₂O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is H, R₃ is        allyl, R₄ is H, R₅ is H, A is absent, Y is CH₂O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is H, R₃ is        phenethyl, R₄ is H, R₅ is H, A is CH₂CH₂, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is H, R₃ is H,        R₄ is H, R₅ is H, A is absent, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is H, R₅ is H, A is absent, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is 1-H-imidazol-5-yl methyl, R₄ is H, R₅ is H, A is CH₂CH₂, Y is        O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is 5-hydroxy, R₅ is H, A is CH₂CH₂, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is 1-H-imidazol-4-ylmethyl, R₄ is H, R₅ is H, A is CH₂CH₂, Y is        S, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is 5-methoxy, R₅ is H, A is CH₂CH₂, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is 5-pyridin-4-yl, R₅ is H, A is CH₂CH₂, Y is O, and Z        is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is 5-furan-3-yl, R₅ is H, A is CH₂CH₂, Y is O, and Z is        O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is 6-hydroxy, R₅ is H, A is CH₂CH₂, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is methyl, R₂ is isopropyl,        R₃ is H, R₄ is H, R₅ is H, A is CH₂CH₂, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is 5-bromo, R₅ is H, A is CH₂CH₂, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is 6-methoxy, R₅ is H, A is CH₂CH₂, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is 6-methyl, R₅ is H, A is CH₂CH₂, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is H, R₅ is H, A is CH₂CH₂, Y is S, and Z is O;    -   a compound of Formula (I) wherein R₁ is n-propyl, R₂ is        n-propyl, R₃ is H, R₄ is H, R₅ is H, A is CH₂CH₂, Y is O, and Z        is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is 7-fluoro, R₅ is H, A is CH₂CH₂, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is 5-pyridin-3-yl, R₅ is H, A is CH₂CH₂, Y is O, and Z        is O;    -   a compound of Formula (I) wherein R₁ is methyl, R₂ is isobutyl,        R₃ is H, R₄ is H, R₅ is H, A is CH₂CH₂, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is methyl, R₂ is n-butyl,        R₃ is H, R₄ is H, R₅ is H, A is CH₂CH₂, Y is O, and Z is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is 5-quinolin-3-yl, R₅ is H, A is CH₂CH₂, Y is O, and Z        is O;    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is 5-thiophen-3-yl, R₅ is H, A is CH₂CH₂, Y is O, and Z        is O; and    -   a compound of Formula (I) wherein R₁ is ethyl, R₂ is ethyl, R₃        is H, R₄ is 5-phenyl, R₅ is H, A is CH₂CH₂, Y is O, and Z is O.

Another embodiment of the present invention is a composition comprisingthe dextrorotatory enantiomer of a compound of formula (I) wherein R₁ isethyl, R₂ is ethyl, R₃ is H, R₄ is H, R₅ is H, A is CH₂CH₂, Y is O, andZ is O; wherein said composition is substantially free from thelevorotatory isomer of said compound. In the present context,substantially free means less than 25%, preferably less than 10%, morepreferably less than 5%, even more preferably less than 2% and even morepreferably less than 1% of the levorotatory isomer calculated as.

${\%\mspace{14mu}{levorotatory}} = {\frac{\left( {{mass}\mspace{14mu}{levorotatory}} \right)}{\left( {{mass}\mspace{14mu}{dextrorotatory}} \right) + \left( {{mass}\mspace{14mu}{levorotatory}} \right)} \times 100}$

Another embodiment of the present invention is a composition comprisingthe levorotatory enantiomer of a compound of formula (I) wherein R₁ isethyl, R₂ is ethyl, R₃ is H, R₄ is H, R₅ is H, A is CH₂CH₂, Y is O, andZ is O; wherein said composition is substantially free from thedextrorotatory isomer of said compound. In the present context,substantially free from means less than 25%, preferably less than 10%,more preferably less than 5%, even more preferably less than 2% and evenmore preferably less than 1% of the dextrorotatory isomer calculated as

${\%\mspace{14mu}{dextrorotatory}} = {\frac{\left( {{mass}\mspace{14mu}{dextrorotatory}} \right)}{\left( {{mass}\mspace{14mu}{dextrorotatory}} \right) + \left( {{mass}\mspace{14mu}{levorotatory}} \right)} \times 100}$

The compounds of the present invention may also be present in the formof pharmaceutically acceptable salts. For use in medicine, the salts ofthe compounds of this invention refer to non-toxic “pharmaceuticallyacceptable salts” (Ref. International J. Pharm., 1986, 33, 201-217; J.Pharm. Sci., 1997 (January), 66, 1, 1). Other salts well known to thosein the art may, however, be useful in the preparation of compoundsaccording to this invention or of their pharmaceutically acceptablesalts. Representative organic or inorganic acids include, but are notlimited to, hydrochloric, hydrobromic, hydriodic, perchloric, sulfuric,nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic,maleic, fumaric, malic, tartaric, citric, benzoic, mandelic,methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic,2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic,salicylic, saccharinic or trifluoroacetic acid. Representative organicor inorganic bases include, but are not limited to, basic or cationicsalts such as benzathine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine, procaine, aluminum, calcium, lithium,magnesium, potassium, sodium and zinc.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds that are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Furthermore, some of the crystalline forms for the compounds may existas polymorphs and as such are intended to be included in the presentinvention. In addition, some of the compounds may form solvates withwater (i.e., hydrates) or common organic solvents, and such solvates arealso intended to be encompassed within the scope of this invention.

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-d-tartaric acid and/or(+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

Even though the compounds of the present invention (including theirpharmaceutically, acceptable salts and pharmaceutically acceptablesolvates) can be administered alone, they will generally be administeredin admixture with a pharmaceutical carrier, excipient or diluentselected with regard to the intended route of administration andstandard pharmaceutical or veterinary practice. Thus, the presentinvention is directed to pharmaceutical and veterinary compositionscomprising compounds of Formula (I) and one or more pharmaceuticallyacceptable carriers, excipients or diluents.

By way of example, in the pharmaceutical and veterinary compositions ofthe present invention, the compounds of the present invention may beadmixed with any suitable binder(s), lubricant(s), suspending agent(s),coating agent(s), and/or solubilising agent(s).

Tablets or capsules of the compounds may be administered singly or twoor more at a time, as appropriate. It is also possible to administer thecompounds in sustained release formulations.

Alternatively, the compounds of the general Formula (I) can beadministered by inhalation or in the form of a suppository or pessary,or they may be applied topically in the form of a lotion, solution,cream, ointment or dusting powder. An alternative means of transdermaladministration is by use of a skin patch. For example, they can beincorporated into a cream consisting of an aqueous emulsion ofpolyethylene glycols or liquid paraffin. They can also be incorporated,at a concentration of between 1 and 10% by weight, into an ointmentconsisting of a white wax or white soft paraffin base together with suchstabilizers and preservatives as may be required.

For some applications, preferably the compositions are administeredorally in the form of tablets containing excipients such as starch orlactose, or in capsules or ovules either alone or in admixture withexcipients, or in the form of elixirs, solutions or suspensionscontaining flavoring or coloring agents.

The compositions (as well as the compounds alone) can also be injectedperenterally, for example intracavernosally, intravenously,intramuscularly or subcutaneously. In this case, the compositions willcomprise a suitable carrier or diluent.

For parenteral administration, the compositions are best used in theform of a sterile aqueous solution which may contain other substances,for example enough salts or monosaccharides to make the solutionisotonic with blood.

For buccal or sublingual administration the compositions may beadministered in the form of tablets or lozenges which can be formulatedin a conventional manner.

By way of further example, pharmaceutical and veterinary compositionscontaining one or more of the compounds of the invention describedherein as the active ingredient can be prepared by intimately mixing thecompound or compounds with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques. The carrier may takea wide variety of forms depending upon the desired route ofadministration (e.g., oral, parenteral). Thus for liquid oralpreparations such as suspensions, elixirs and solutions, suitablecarriers and additives include water, glycols, oils, alcohols, flavoringagents, preservatives, stabilizers, coloring agents and the like; forsolid oral preparations, such as powders, capsules and tablets, suitablecarriers and additives include starches, sugars, diluents, granulatingagents, lubricants, binders, disintegrating agents and the like. Solidoral preparations may also be coated with substances such as sugars orbe enteric-coated so as to modulate the major site of absorption. Forparenteral administration, the carrier will usually consist of sterilewater and other ingredients may be added to increase solubility orpreservation. Injectable suspensions or solutions may also be preparedutilizing aqueous carriers along with appropriate additives.

Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, compoundsfor the present invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal skinpatches well known to those skilled in that art. To be administered inthe form of a transdermal delivery system, the dosage administrationwill, of course, be continuous rather than intermittent throughout thedosage regimen.

It is also apparent to one skilled in the art that the therapeuticallyeffective dose for active compounds of the invention or a pharmaceuticalcomposition thereof will vary according to the desired effect.Therefore, optimal dosages to be administered may be readily determinedand will vary with the particular compound used, the mode ofadministration, the strength of the preparation, and the advancement ofthe disease condition. In addition, factors associated with theparticular subject being treated, including subject age, weight, dietand time of administration, will result in the need to adjust the doseto an appropriate therapeutic level. The above dosages are thusexemplary of the average case. There can, of course, be individualinstances where higher or lower dosage ranges are merited, and such arewithin the scope of this invention.

Compounds of this invention may be administered in any of the foregoingcompositions and dosage regimens or by means of those compositions anddosage regimens established in the art whenever use of the compounds ofthe invention as analgesics or anti-pyretics is required for a subjectin need thereof.

The invention also provides a pharmaceutical or veterinary pack or kitcomprising one or more containers filled with one or more of theingredients of the pharmaceutical and veterinary compositions of theinvention. Optionally associated with such container(s) can be a noticein the form prescribed by a governmental agency regulating themanufacture, use or sale of pharmaceuticals or biological products,which notice reflects approval by the agency of manufacture, use or salefor human administration.

The compounds of the present invention may be used to treat mild tomoderately severe pain in warm-blooded animals such as humans byadministration of an analgesically effective dose. The dosage rangewould be from about 0.01 mg to about 15,000 mg, in particular from about0.1 mg to about 3500 mg or, more particularly from about 0.1 mg to about1000 mg of active ingredient in a regimen of about 1 to 4 times per dayfor an average (70 kg) human; although, it is apparent to one skilled inthe art that the therapeutically effective amount for active compoundsof the invention will vary as will the types of pain being treated.

For oral administration, a pharmaceutical composition is preferablyprovided in the form of tablets containing, 0.01, 10.0, 50.0, 100, 150,200, 250 and 500 milligrams of the active ingredient for the symptomaticadjustment of the dosage to the subject to be treated.

Examples of pain intended to be within the scope of the presentinvention include, but are not limited to, inflammatory pain, centrallymediated pain, peripherally mediated pain, structural or soft tissueinjury related pain, progressive disease related pain, neuropathic painand acute pain such as caused by acute injury, trauma or surgery andchronic pain such as headache and that caused by neuropathic conditions,post-stroke conditions and migraine.

Compounds of the present invention are also useful asimmunosuppressants, antiinflammatory agents, agents for the treatmentand prevention of neurological and psychiatric conditions, for instance,depression and Parkinson's disease, medicaments for drug and alcoholabuse, agents for treating gastritis and diarrhea, cardiovascular agentsand agents for the treatment of respiratory diseases.

The compounds of the present invention are also useful in treating paincaused by osteoarthritis, rheumatoid arthritis, fibromyalgia, migraine,headache, toothache, burn, sunburn, snake bite (in particular, venomoussnake bite), spider bite, insect sting, neurogenic bladder, benignprostatic hypertrophy, interstitial cystitis, rhinitis, contactdermatitis/hypersensitivity, itch, eczema, pharyngitis, mucositis,enteritis, cellulites, causalgia, sciatic neuritis, mandibular jointneuralgia, peripheral neuritis, polyneuritis, stump pain, phantom limbpain, post-operative ileus, cholecystitis, postmastectomy pain syndrome,oral neuropathic pain, Charcot's pain, reflex sympathetic dystrophy,Guillain-Barre syndrome, meralgia paresthetica, burning-mouth syndrome,post-herpetic neuralgia, trigeminal neuralgia, cluster headache,migraine headache, peripheral neuropathy, bilateral peripheralneuropathy, diabetic neuropathy, postherpetic neuralgia, trigeminalneuralgia, optic neuritis, postfebrile neuritis, migrating neuritis,segmental neuritis, Gombault's neuritis, neuronitis, cervicobrachialneuralgia, cranial neuralgia, geniculate neuralgia, glossopharyngialneuralgia, migrainous neuralgia, idiopathic neuralgia, intercostalsneuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia,occipital neuralgia, red neuralgia, Sluder's neuralgia, splenopalatineneuralgia, supraorbital neuralgia, vidian neuralgia, sinus headache,tension headache, labor, childbirth, menstrual cramps, and cancer.

In regard to the use of the present compounds in treatment of thediseases or conditions such as those listed above, a therapeuticallyeffective dose can be determined by persons skilled in the art by theuse of established animal models. Such a dose would likely fall in therange of from about 0.01 mg to about 15,000 mg of active ingredientadministered 1 to 4 times per day for an average (70 kg) human.

General Synthetic Methods

Representative compounds of the present invention can be synthesized inaccordance with the general synthetic methods described below and areillustrated in the schemes that follow. Since the schemes are anillustration, the invention should not be construed as being limited bythe chemical reactions and conditions expressed. The preparation of thevarious starting materials used in the schemes is well within the skillof persons versed in the art.

The preparation of compounds of this invention is illustrated in Schemes1 and 2. Both schemes proceed with the same overall strategy. In stage1, an intermediate 1 is prepared with two benzene rings connected by alinker —Y—. The linker —Y— should be of the form —(CH₂)_(n)—X— where Xmay be oxygen or sulfur and n may be zero or one. One benzene ring bearsa group, Q, which is a group readily transformable to a carboxylic acidamide. Examples of such Q groups are fluoro, bromo, iodo ortrifluoromethanesulfonyloxy. One benzene ring must bear a carboxylicacid ortho to the linker —Y—. The atom X may be attached either to thebenzene ring bearing the Q group or the benzene ring lacking the Qgroup. Schemes 1 and 2 differ in that in scheme 1, the carboxylic acidis on the benzene ring bearing the Q group (1A and 1B) while in scheme 2the carboxylic acid function is on the benzene ring which does not bearthe group Q (1C, D and E).

In stage 1 the linker —Y— is constructed between two monocyclicintermediates. For Scheme 1, Stage 1 the bridge may be constructed bynucleophilic aromatic displacement of fluoride from intermediate int 2(where Q′ is an electron withdrawing group, readily convertible to acarboxylic acid, for instance cyano or carbalkoxy) by a phenoxide,thiophenoxide, benzyloxide or thiobenzyloxide, int 1. The 1A compoundsare then obtained by hydrolysis with an alkali metal hydroxide. Forconstruction of the bridge of compounds of type 1B, a benzyl halideintermediate compound (int 5) is prepared by NBS bromination of thecorresponding toluene (int 4). Reaction of int 5 with a phenoxide orthiophenoxide leads to int 6. The 1B compound may be obtained by alkalimetal hydroxide hydrolysis of int 6.

For Scheme 2, Stage 1 in order to prepare 1C compounds, a phthalide (int7) may be caused to react with a phenoxide or thiophenoxide (int 8). Forpreparation of 1D compounds, the bridge may be constructed bynucleophilic aromatic displacement of fluoride from intermediate int 9by phenoxides or thiophenoxides (int 8). The 1D compounds are thenobtained by hydrolysis of int 10 with an alkali metal hydroxide. Forconstruction of the bridge of compounds of type 1E, reaction of a benzylbromide intermediate compound (int 12) with a phenoxide or thiophenoxide(int 11) leads to int 13. The 1E compound may then be obtained byhydrolysis of int 13 with an alkali metal hydroxide.

Following Stage 1, the schemes merge. In Stage 2 compounds 1 areconverted by cycloacylation to ketones 2, using, for instance,BF₃.Et₂O-trifluoroacetic acid or polyphosphoric acid. Alternatively thecyclization may be effected by converting acid 1 to an acid chloride,for instance with thionyl chloride, followed by Friedel-Crafts ringclosure in the presence of a Lewis acid, such as aluminum chloride.

In addition, Stages 1 and 2 may be performed in reverse to givecompounds 2 that are ready to enter Stage 3. For instance,cycloacylation between a methyl ether (int 14) and an appropriatelysubstituted acid chloride provides the ketone (int 16) which has beensimultaneously demethylated under the Friedel-Crafts reactionconditions. Subsequent formation of the bridge —Y— via a nucleophilicaromatic displacement gives compounds 2 ready to enter Stage 3.

In stage 3, the Q function of compounds 2 is converted into carboxylicacid amide group to give compounds of formula 3. This may beaccomplished by first conversion to an ester by alkoxycarbonylation, forinstance, with carbon monoxide, an aliphatic alcohol, a trialkanyl amineand a palladium catalyst such as bis(triphenylphosphine)palladium(II)dichloride. The ester may be hydrolyzed to an acid andfinally converted to a primary, secondary or tertiary amide by acoupling reaction with ammonia, a primary amine, or a secondary amine.The conversion of acid to amide may be carried out by first conversionto an acid chloride, for instance, using thionyl chloride, followed bySchotten-Baumann reaction using ammonia or an amine and alkali metalhydroxide. Alternatively, the ester may be converted directly to theamide by the action of a dimethylaluminum amide. Instead of proceedingto compounds 3 via an ester, one may effect the transformation of thegroup Q into a carboxylic acid amide by way of a nitrile. Synthesis ofthe nitrile may be accomplished by treatment of the compounds 2 withZn(CN)₂ and a palladium catalyst such as (Ph₃P)₄Pd or by treatment ofthe compounds 2 with CuCN at elevated temperature. The nitrile ishydrolyzed using an alkali metal hydroxide yielding the same acid asderived from the ester.

To perform stage 4, a 4-piperidinylidene or 8-tropanylidene function isattached to the tricyclic system, replacing the ketone to give compoundsof type 4 (in the piperidinylidene case the function -A- does not existwhile in the tropanylidene case it represents —(CH₂)₂—). This operationmay be carried out by McMurray condensation of ketones 3 with4-piperidinones or 8-tropinones brought about by a lower valent titaniumreagent such as the reagent obtained from addition of titaniumtetrachloride to zinc dust. Alternatively, a 4-piperidinyl magnesiumhalide or 8-tropanylidenylmagnesium halide may be added to ketone toafford carbinols. Dehydration of such carbinols with acidic reagentssuch as formic acid, sulfuric acid or trifluoroacetic acid gives rise tocompounds of type 4.

If desired, the operation of stages 3 and 4 may be carried out inreverse order.

As illustrated in Schemes 1 and 2, the nitrogen atoms of compounds 4bear a group P. This group may be an alkanyl, alkenyl or aralkanyl inwhich case they are the therapeutically useful products of thisinvention. The group P may also be alkoxycarbonyl or aralkoxycarbonyl.The latter groupings can be converted to secondary amines 5 asillustrated for Stage 5. These transformations may be carried out usingcertain acidic reagents such as hydrogen bromide or trimethylsilyliodide. Compounds of type 4 bearing readily cleavable groups such asmethyl, allyl or benzyl may be transformed into the aforementionedalkoxycarbonyl derivatives by treatment with alkanylchloro-formates suchas ethyl chloroformate or 1-choroethyl chloroformate and thus serve assources of compounds 5.

Finally the secondary amines 5 may be converted to any desired endproduct of the invention 6 as shown in Stage 6. These transformationsmay be carried out by reductive alkylation using a carbonyl compound anda reducing agent such as sodium borohydride, sodium cyanoborohydride orsodium triacetoxyborohydride. They may also be carried out by alkyationusing a alkanyl, alkenyl or arakyl halide and an organic or inorganicbase.

Desired end products of the present invention may include chemicalmodifications at R₄. Such transformations may include the dealkylationof lower alkyl ethers to give the corresponding alcohols using reagentssuch as boron trihalides. Compounds where R₄ is a halogen atom mayparticipate in transition metal-mediated coupling reactions such asSuzuki, Stille or Negishi chemistry.

The compounds wherein the bridge -A- is —(CH₂)₂— are chiral. They may beseparated into their enantiomers by chromatography on a chiralstationary phase following Stages 4, 5, or 6. Alternatively, the basiccompounds of types 4, 5, and 6 may be converted to diastereomeric saltsby mixture with a chiral acid and resolved into their enantiomers byfractional crystallization.

It is generally preferred that the respective product of each processstep be separated from other components of the reaction mixture andsubjected to purification before its use as a starting material in asubsequent step. Separation techniques typically include evaporation,extraction, precipitation and filtration. Purification techniquestypically include column chromatography (Still, W. C. et. al., J. Org.Chem. 1978, 43, 2921), thin-layer chromatography, crystallization anddistillation. The structures of the final products, intermediates andstarting materials are confirmed by spectroscopic, spectrometric andanalytical methods including nuclear magnetic resonance (NMR), massspectrometry (MS) and liquid chromatography (HPLC). In the descriptionsfor the preparation of compounds of this invention, ethyl ether,tetrahydrofuran and dioxane are common examples of an ethereal solvent;benzene, toluene, hexanes and cyclohexane are typical hydrocarbonsolvents and dichloromethane and dichloroethane are representativehalogenhydrocarbon solvents. In those cases where the product isisolated as the acid addition salt the free base may be obtained bytechniques known to those skilled in the art. In those cases in whichthe product is isolated as an acid addition salt, the salt may containone or more equivalents of the acid.

Enantiomers of the compounds of the present invention may be separatedusing chiral HPLC.

Representative compounds of the present invention can be synthesized inaccordance with the general synthetic methods described above and areillustrated more particularly in the schemes that follow. Since theschemes are illustrations, the invention should not be construed asbeing limited by the chemical reactions and conditions expressed. Thepreparation of the various starting materials used in the schemes iswell within the skill of persons versed in the art.

EXAMPLES Example A

Procedure 1 4-Bromo-2-phenoxy-benzonitrile, 1a

Sodium hydride (12 g, 300 mmol) (60% by wt) was weighed into a flask andwashed free of oil with several hexane rinsings. The hexanes weredecanted and discarded and DMF was added to the flask. A DMF-solution ofphenol (23.5 g, 250 mmol in 100 mL DMF) was added dropwise to the NaHmixture and stirred at room temperature. To the phenoxide was added asolution of 4-bromo-2-fluoro-benzonitrile (50 g, 250 mmol in 100 mLDMF), dropwise. Upon complete addition, the reaction was refluxed for 20h. The reaction was cooled to room temperature, and poured into cold 1 NNaOH. A fine, tan precipitate formed and was collected by vacuumfiltration to give 62.04 g (226 mmol) of Compound 1a. MS m/z (MH⁺) 277.

Procedure 2 4-Bromo-2-phenoxy-benzoic acid, 2a

4-Bromo-2-phenoxy-benzonitrile (35.3 g, 129 mmol) was added to 130 mLEtOH, followed by the addition of 340 mL of 20% NaOH (aq). The reactionwas heated to reflux for 20 h. The mixture was cooled to roomtemperature and poured into 6 N HCl to form a precipitate. The solid wascollected by vacuum filtration and dissolved in 3:1 THF-ethyl ether andwashed with brine. The organic phase was dried over magnesium sulfate,and concentrated. The solids were dried in a vacuum oven at 60° C.overnight to give 35.1 g (128 mmol) of the desired product. MS m/z (MH⁺)292.

Procedure 3 3-Bromo-xanthen-9-one, 3a

To a suspension of 4-bromo-2-phenoxy-benzoic acid (35.1 g, 120 mmol) inCH₂Cl₂ (350 mL) at 0° C. was added trifluoroacetic anhydride (20.3 mL,144 mmol), dropwise, and the reaction was stirred for 15 min. At thattime, boron trifluoride diethyl etherate (1.46 mL, 12.0 mmol) was added,dropwise. The reaction became homogeneous upon stirring for 1 h at roomtemperature. Upon completion, the reaction was poured into 1 N NaOH, andthe organic phase was dried over magnesium sulfate, filtered, andconcentrated to give Compound 3a (32.14 g, 116 mmol). MS m/z (MH⁺) 275.

Procedure 4 9-Oxo-9H-xanthene-3-carboxylic acid methyl ester, 4a

A sample of Compound 3a (20 g, 72.2 mmol) was dissolved in a 2:1MeOH/DMF solution (600 mL). To this solution was added triethylamine (40mL, 290 mmol) and the solution was degassed with Argon. To this wasadded dichlorobis(triphenylphosphine) palladium (II) (2.0 g, 2.85 mmol),and the reaction was transferred to a bomb and charged with 150 psi ofCO (g). The reaction was stirred at 90° C. for 24 h. Upon completion,the reaction was cooled to 40° C. and CH₂Cl₂ was added. The reaction wasfiltered while warm and evaporated to provide the crude product.Recrystallization from ethanol gave 16.62 g (65.4 mmol) of Compound 4a.MS m/z (MH⁺) 255.

Procedure 5 9-Oxo-9H-xanthene-3-carboxylic acid, 5a

A sample of 9-Oxo-9H-xanthene-3-carboxylic acid methyl ester, compound4a, (16.6 g, 65.3 mmol) was suspended in 250 mL of 3 N NaOH and 250 mLof EtOH and heated to reflux for 1 h. At that time the EtOH wasevaporated and the reaction was poured into 6 N HCl over ice andextracted with large volumes of 1:1 THF/diethyl ether. The combinedorganic phases were washed with brine, dried over magnesium sulfate,filtered and evaporated to provide 13.35 g of Compound 5a (55.6 mmol)after drying in a vacuum oven at 50° C. overnight.

Procedure 6 9-Oxo-9H-xanthene-3-carboxylic acid diethylamide, 6a

A sample of compound 5a, (13.4 g, 55.6 mmol) was suspended in 220 mLCH₂Cl₂ and 24.4 mL (330 mmol) of thionyl chloride was added. The mixturewas refluxed over 6 h, adding approximately 10 mL of additional thionylchloride per hour until the reaction became homogeneous. At that time,the thionyl chloride and solvent were removed under vacuum and theremaining residue was diluted with an additional 220 mL CH₂Cl₂. To thesuspension was added 100 mL ice cold 1.5 N NaOH, 100 mL CH₂Cl₂, and 17mL (166 mmol) diethyl amine. After stirring for 15 min at roomtemperature, the phases were separated, and the organic phase was washedwith HCl and brine, dried over magnesium sulfate, filtered andconcentrated to yield Compound 6a (14.7 g, 49.8 mmol). MS m/z (MH⁺) 296.

9-Oxo-9H-xanthene-3-carboxylic acid ethylamide, 7a

Following Procedure 6, substituting ethylamine for diethylamine,compound 6a was converted into its monoethyl amide. MS m/z (MH⁺) 267.9.

Procedure 73-(3-Diethylcarbamoyl-xanthen-9-ylidene)-8-aza-bicyclo[3.2.1]octane-8-carboxylicacid ethyl ester, 8a

A suspension of zinc metal dust (24.2 g, 370 mmol) in THF (325 mL) underArgon at 5° C. was treated with titanium (IV) tetrachloride (20.3 mL,180 mmol), dropwise. The reaction was then refluxed for 2 h. The heatwas removed and a solution of compound 6a (13.69, 46 mmol), andN-carbethoxynortropinone (9.21 g, 46 mmol) in 100 mL THF was addeddropwise. The reaction was refluxed for another 2 h. At that time thereaction was cooled and added to excess potassium carbonate in icewater. The mixture was extracted with EtOAc and the combined extractswere washed with brine, dried over magnesium sulfate, filtered andevaporated to give 22 g of a gum. This crude product was chromatographedusing 1:1 EtOAc/hexanes to provide 17 g (36.9 mmol) of Compound 8a. MSm/z (MH⁺) 461.8.

9-(8-Phenethyl)-8-aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-3-carboxylicacid ethylamide, 9a

The title compound was synthesized following Procedure 7, substitutingcompound 7a for compound 6a and substituting N-phenethyl-4-tropinone forcarbethoxynortropinone. MS m/z=465.1 (M+1); ¹H NMR 300 MHz (DMSO-d₆) δ1.1 (t, 3H), 1.3 (m, 2H), 2.1 (m, 2H), 2.5 (q, 2H), 3.0-3.4 (m, 8H),4.05 (m, 2H), 7.1-7.7 (m, 11H), 8.5 (m, 1H).

Procedure 89-(8-Aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-3-carboxylic aciddiethylamide, 10a

A sample of compound 8a (16.0 g, 34.8 mmol) was dissolved in 35 mLacetic acid and 100 mL of 30% HBr in acetic acid was added to thereaction under Argon before heating on a steam bath for 1 h. Thereaction was cooled, added to ice cold NaOH and extracted with CH₂Cl₂.The combined organics were washed with brine and dried over potassiumcarbonate. Evaporation of the solvent provided 12 g of crude Compound10a, which was purified by column chromatography with 7% 2 N NH₃ inmethanol/93% CH₂Cl₂. to give 7.66 g (19.7 mmol) of Compound 10a. MSm/z=389.3 (M+1); ¹H NMR 300 MHz (CDCl₃) δ 1.1-1.4 (m, 6H), 1.7 (m, 2H),2.7-3.0 (m, 4H), 3.4 (br s, 4H), 3.5-3.7 (m, 4H), 7.0-7.3 (m, 7H).

9-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-3-carboxylicacid diethylamide, 11a

Following Procedure 7 and substituting tropinone forN-carbethoxynortropinone, compound 6a was converted to the titlecompound. MS m/z=403.2 (M+1); ¹H NMR 300 MHz (CDCl₃) δ 1.2 (br s, 6H),1.9 (m, 2H), 2.5 (s, 3H), 2.8 (m, 2H), 3.1 (m, 2H), 3.3 (m, 2H), 3.4 (brs, 2H), 3.6 (m, 4H), 7.0-7.3 (m, 7H).

Procedure 99-(8-Furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-3-carboxylicacid diethylamide, 12a

To a sample of compound 10a (0.65 g, 1.7 mmol) dissolved in 20 mL CH₂Cl₂was added sodium triacetoxyborohydride (0.53 g, 2.5 mmol) and3-furaldehyde (0.17 mL, 2.0 mmol). The reaction was stirred at roomtemperature for 24 h. The reaction was diluted with 10 mL CH₂Cl₂ andwashed with 1 N NaOH. The organic phase was dried over sodium sulfate,filtered, and concentrated. The crude product was purified by flashchromatography, eluting with 5% 0.5 M NH₃ in methanol/CH₂Cl₂ to giveCompound 12a (0.25 g, 0.53 mmol). MS m/z=469.0 (M+1); ¹H NMR 300 MHz(DMSO-d₆) δ 1.1 (br s, 6H), 1.35 (m, 2H), 2.1 (m, 2H), 2.5 (m, 2H), 3.0(m, 2H), 3.2 (m, 2H), 3.5 (m, 2H), 3.85 (br s, 2H), 4.05 (d, 2H), 6.8(s, 1H), 7.1-7.5 (m, 7H), 7.8 (s, 1H), 7.9 (s, 1H).

Procedure 109-[8-(Methylsulfanyl-ethyl)-8-aza-bicyclo[3.2.1]oct-3-ylidene]-9H-xanthene-3-carboxylicacid diethylamide, 13a

A solution of p-toluenesulfonic acid monohydrate (1.4 g, 7.5 mmol) in 20mL water was added to a stirred solution of (methylthio)acetaldehydedimethyl acetal (1.0 mL, 7.5 mmol) in 15 mL CH₂Cl₂ and the reaction wasvigorously stirred for 4 h. The aqueous phase was separated andsaturated with NaCl, then extracted with CH₂Cl₂. The organic extractswere washed with saturated aqueous sodium bicarbonate and then withbrine. The extracts were then dried over magnesium sulfate and filtered.To the filtrate was added compound 10a (0.060 g, 0.15 mmol) and sodiumtriacetoxyborohydride (0.040 g, 0.19 mmol) and the reaction was stirredat room temperature overnight. The reaction was washed with 1 M NaOH andthe organic phase was dried over magnesium sulfate. The solution wasconcentrated and purified on silica gel using flash chromatography. Theproduct eluted with 10% 0.5 M NH₃ in methanol/CH₂Cl₂ and wasconcentrated. Trituration from chloroform and diethyl ether providedpure Compound 13a (0.040 g. 0.086 mmol). MS m/z=463.8 (M+1).

Procedure 119-(8-Allyl-8-aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-3-carboxylicacid diethylamide, 14a

To a sample of compound 10a (0.37 g, 0.95 mmol) in 6 mL acetonitrile wasadded potassium carbonate (0.53 g, 3.81 mmol) and allyl bromide (80 μL,0.95 mmol). The mixture was stirred at room temperature for 20 h. Thereaction was diluted with water and extracted with CH₂Cl₂. The combinedorganic extracts were dried over magnesium sulfate and concentrated. Theproduct was purified by flash column chromatography on silica gel,eluting with 10% 0.5 M NH₃ in methanol/CH₂Cl₂ to yield 0.11 g (0.25mmol) of Compound 14a. The product was converted into its HCl salt usingethereal hydrogen chloride. MS m/z=429.0 (M+1); ¹H NMR 300 MHz (CDCl₃) δ1.1-1.4 (m, 6H), 1.7 (m, 2H), 2.3 (m, 2H), 3.1 (m, 2H), 3.4 (m, 2H), 3.6(m, 4H), 4.0 (m, 2H), 4.4 (m, 2H), 4.7 (m, 2H), 5.5-5.9 (m, 4H), 6.3 (m,2H), 7.1-7.4 (m, 7H).

9-[8-(2-Methoxy-ethyl)-8-aza-bicyclo[3.2.1]oct-3-ylidene]-9H-xanthene-3-carboxylicacid diethylamide, 15a

Following Procedure 11 and substituting 3 equivalents of 2-bromoethylmethyl ether for allyl bromide, compound 10a was converted to titlecompound 15a. The product was converted into its HCl salt using etherealhydrogen chloride. MS m/z=447.4 (M+1); ¹H NMR 300 MHz (CDCl₃) δ 1.0-1.2(m, 6H), 1.3 (m, 2H), 2.0 (m, 2H), 2.95 (m, 2H), 3.1-3.2 (m, 2H), 3.3(s, 3H), 3.4 (m, 2H), 3.6 (m, 4H), 3.8 (m, 2H), 4.0 (m, 2H), 7.1-7.4 (m,7H).

Example B

9-Piperidin-4-ylidene-9H-xanthene-3-carboxylic acid diethylamide,fumarate 1b

Following Procedure 7, substituting N-Boc-piperidone forN-carbethoxynortropinone, the Compound 1b was synthesized in one stepfrom compound 6a with the simultaneous removal of the Boc-protectinggroup. Purification was performed on silica gel using flashchromatography. The product eluted with 10% 2 N NH₃ in methanol/CH₂Cl₂.A fumarate salt was prepared from 2-PrOH. MS m/z (MH⁺) 363.2; ¹H NMR 300MHz (DMSO-d₆) δ 1.1 (br s, 6H), 2.8 (m, 4H), 2.95 (m, 4H), 3.3, 3.4 (brs, 4H), 6.4 (s, 2H) 7.1-7.5 (m, 7H).

9-Piperidin-4-ylidene-9H-xanthene-3-carboxylic acid ethylamide, 2b

Following Procedure 7, substituting compound 7a for compound 6a andsubstituting N-Boc-piperidone for N-carbethoxynortropinone, the titlecompound 2b was synthesized. MS m/z (MH⁺) 334.8.

9-(1-Furan-3-ylmethyl-piperidin-4-ylidene)-9H-xanthene-3-carboxylic aciddiethylamide, Hydrochloride 3b

Following Procedure 9, compound 1b was converted to the title compound3b. The crude product was purified by flash chromatography on silicagel, eluting with 3% methanol/CH₂Cl₂ to yield the product. Ahydrochloride salt was prepared from Et₂O/HCl. MS m/z (MH⁺) 363.2; ¹HNMR 300 MHz (DMSO-d₆) δ 1.2 (br d, 6H), 2.4 (m, 2H), 3.3-3.6 (m, 10H),4.0 (s, 2H), 6.8 (s, 1H) 7.1-7.3 (m, 7H), 7.5 (s, 1H), 7.7 (s, 1H), 13.1(s, 1H).

Procedure 129-(1-Carbamimidoyl-piperidin-4-ylidene)-9H-xanthene-3-carboxylic aciddiethylamide, 4b

A solution of compound 2b, (0.025 g, 0.069 mmol) and c (0.015 g, 0.36mmol) were refluxed in 4 mL water. After 3 h, the reaction was 50%complete. Additional cyanamide was added and the mixture was heated foran additional 24 h. The reaction was cooled to room temperature andconcentrated under vacuum. Purification of the crude material wasperformed by HPLC, 15-70% acetonitrile/water/0.1% TFA. The TFA salt ofCompound 4b was isolated (1.4 mg, 3.5 μmol). MS m/z=405.1 (M+1); ¹H NMR300 MHz (DMSO-d₆) δ 1.1 (br s, 6H), 2.8 (m, 4H), 3.2 (m, 2H), 3.5 (m,6H), 7.1-7.5 (m, 7H).

9-(R³-piperidin-4-ylidene)-9H-xanthene-3-carboxylic acid diethylamide,5b-8b

Following Procedure 9, substituting the appropriate aldehyde for3-furaldehyde, the following compounds were prepared:

MS m/z Ex # Aldehyde R³ (MH⁺) 5b 2-pyridinecarboxaldehyde Pyridin-2-ylmethyl 454.5 6b salicylaldehyde 2-Hydroxy benzyl 469.2 7b formalinMethyl 377.26 8b phenylacetaldehyde Phenethyl 467.33

9-(1-Prop-2-ynyl-piperidin-4-ylidene)-9H-xanthene-3-carboxylic aciddiethylamide Hydrochloride, 9b

Following Procedure 11, substituting propargyl bromide for allylbromide, compound 1b was refluxed for 12 h in acetonitrile. The crudeproduct was purified by flash column chromatography on silica gel,eluting with 3% methanol/CH₂Cl₂, and then converted to its hydrochloridesalt with ethereal hydrogen chloride. MS m/z (MH⁺) 401.4; ¹H NMR 300 MHz(CDCl₃) δ 1.2 (br d, 6H), 2.6 (s, 1H), 2.9 (m, 2H) 3.1-3.6 (m, 10H), 3.9(s, 2H),) 7.15-7.3 (m, 7H), 13.5 (s, 1H).

9-[1-(2-Hydroxy-ethyl)-piperidin-4-ylidene]-9H-xanthene-3-carboxylicacid diethylamide, 10b

Following Procedure 11, substituting 2-iodo-ethanol for allyl bromide,the title compound was prepared from compound 1b. MS m/z (MH⁺) 407.0; ¹HNMR 300 MHz (CDCl₃) δ 1.2 (br d, 6H), 1.7 (m, 2H), 2.8 (m, 2H), 3.1 (m,2H), 3.2-3.8 (m, 8H), 4.0 (m, 2H), 4.8 (m, 1H), 7.15-7.3 (m, 7H).

Procedure 139-(1-Thioformyl-piperidin-4-ylidene)-9H-xanthene-3-carboxylic aciddiethylamide, 11b

A sample of compound 1b (0.77 g, 2.1 mmol) was refluxed in 2 mL toluenewith N,N-dimethyl-thioformamide (0.36 mL, 4.24 mmol) for 5 h. The crudeproduct was purified on a flash column through silica gel, eluting with45% ethyl acetate in hexanes to yield 0.66 g (1.6 mmol) of Compound 11b.Two rotamers were observed by ¹H-NMR. MS m/z (MH⁺) 406.9. ¹H NMR 300 MHz(CDCl₃) δ 1.2 (br d, 6H), 2.9 (m, 3H), 3.3 (m, 2H) 3.4-3.7 (m, 3H), 3.9(m, 2H), 7.1-7.4 (m, 7H), 9.3 (s, 1H).

Procedure 149-(1-Phenyliminomethyl-piperidin-4-ylidene)-9H-xanthene-3-carboxylicacid diethylamide, 12b

A sample of compound 11b (0.1 g, 0.25 mmol) in 1 mL of chloroform wasplaced in a pressure tube and treated with methyl tosylate (0.037 mL,0.25 mmol). The reaction was heated for 1 h on a steam bath. At thattime the reaction was cooled to room temperature and aniline (0.023 mL,0.25 mmol) was added, and the reaction was heated again on a steam bathfor another 2 h. After 2 h, the reaction was cooled, washed with 1 NNaOH, and evaporated. Flash chromatography on silica gel was used topurify the crude material, eluting the product with 5% methanol/CH₂Cl₂,followed by conversion to its hydrochloride salt with ethereal hydrogenchloride (0.004 g, 0.009 mmol). MS m/z (MH⁺) 466.3. ¹H NMR 300 MHz(CDCl₃) δ 1.2 (br s, 6H), 3.1 (m, 4H), 3.3 (d, 2H) 3.4-3.8 (m, 4H), 4.3(s, 2H),) 7.1-7.4 (m, 10H), 7.7 (s, 2H), 8.0 (s, 1H), 13.6 (s, 1H).

9-(1-Allyl-piperidin-4-ylidene)-9H-xanthene-3-carboxylic aciddiethylamide, 13b

Following Procedure 11, and substituting compound 1b for Compound 10a,Compound 1b was converted to the title compound 13b. MS m/z (MH⁺) 403.3¹H NMR 300 MHz (CDCl₃) δ 1.2 (br d, 6H), 2.5 (m, 2H), 3.1-3.7 (m, 12H),5.4 (m, 2H),) 6.2 (m, 1H), 7.1-7.3 (m, 7H).

Example C

Procedure 15 2-(3-Bromo-phenoxymethyl)-benzoic acid, 1c

A solution m-bromo-phenol (9.4 mL, 0.100 mmol) in 25 mL THF was addeddropwise to sodium hydride (4.0 g, 0.10 mmol) from which the oil hadbeen washed with hexanes. When the bubbling had stopped, the solvent wasevaporated and phthalide (13 g, 0.1 mmol) was added. The reaction washeated to 200° C. in an oil bath for 1 h. The reaction was cooled,diluted with water, washed with ethyl ether, and acidified with HCl. Thesolid was collected and air-dried to yield 22.3 g (72.9 mmol) ofCompound 1c. MS m/z 305.31 (M-H).

3-Bromo-6H-dibenzo[b,e]oxepin-11-one, 2c

Compound 1c (22.3 g, 72.6 mmol) was converted to the title compound 2c(15.2 g, 52.3 mmol) using an adaptation of Procedure 3. MS m/z (MH⁺)289.

11-Oxo-6,11-dihydro-dibenzo[b,e]oxepine-3-carboxylic acid methyl ester,3c

A sample of compound 2c (5.0 g, 17 mmol) was converted into the desiredmethyl ester (3.0 g, 11.2 mmol) using an adaptation of Procedure 4.

11-Oxo-6,11-dihydro-dibenzo[b,e]oxepine-3-carboxylic acid, 4c

A sample of compound 3c (6.0 g, 22 mmol) was converted to thecorresponding carboxylic acid (5.5 g, 21.6 mmol) using an adaptation ofProcedure 5.

11-Oxo-6,11-dihydro-dibenzo[be]oxepine-3-carboxylic acid diethylamide,5c

A sample of compound 4c (5.5 g, 21.6 mmol) was converted to itscorresponding diethylamide (4.28 g, 13.8 mmol) following an adaptationof Procedure 6.

11-(1-Methyl-piperidin-4-ylidene)-6,11-dihydro-dibenzo[b,e]oxepine-3-carboxylicacid diethylamide, 0.5 Fumarate, 6c

A sample of compound 5c was converted to the title compound followingProcedure 7, substituting compound 5c (3.85 g, 12.5 mmol) for compound6a and substituting N-methyl-piperidone for N-carbethoxynortropinone.The reaction yielded 2.5 g (6.4 mmol) of Compound 6c. MS m/z (MH⁺)391.28; ¹H NMR 300 MHz (DMSO) δ 1.0 (br s, 6H), 2.5 (m, 2H), 3.1-3.7 (m,12H), 5.4 (m, 2H),) 6.2 (m, 1H), 7.1-7.3 (m, 7H).

Procedure 164-(3-Diethylcarbamoyl-6H-dibenzo[b,e]oxepin-11-ylidene)-piperidine-1-carboxylicacid 2,2,2-trichloro-ethyl ester, 7c

A sample of compound 6c (2.58 g, 6.41 mmol), trichloroethylchloroformate (1.33 mL, 9.7 mmol) and potassium carbonate (3.34 g, 24.2mmol) were refluxed for 3.5 h in benzene. An additional 4 mL oftrichloroethyl chloroformate was added and the reaction was refluxed foranother hour. Dimethyl aminopropylamine (5 mL) was added, and thereaction went to completion. The mixture was extracted with 2 N HCl,washed with brine, and the organic phase was dried over magnesiumsulfate, filtered and then evaporated. The crude product wasrecrystallized from acetone/hexane to give 2 g (3.6 mmol) of Compound7c. MS m/z (MH⁺) 551.31.

Procedure 1711-Piperidin-4-ylidene-6,11-dihydro-dibenzo[b,e]oxepin-11-ylidene-piperidine-1-carboxylicacid diethylamide, 8c

A sample of compound 7c (1.75 g, 3.17 mmol) and zinc (1.51 g, 23.1 mmol)was stirred in acetic acid (17.5 mL) at room temperature. The resultingsolids were collected by filtration and washed with additional aceticacid. The filtrate was concentrated, partitioned between NaOH andCH₂Cl₂. The organic phase was collected and dried over potassiumcarbonate, and evaporated. The crude product was recrystallized fromacetonitrile to give Compound 8c (1.2 g, 3.2 mmol). MS m/z (MH⁺) 377.28;¹H NMR 300 MHz (CDCl₃) δ 1.2 (br d, 6H), 2.3 (m, 2H), 2.4-3.1 (m, 6H)3.4 (br d, 4H), 4.8 (d, 1H),) 5.8 (d, 1H) 6.8 (d, 1H), 7.0 (m, 1H), 7.1(d, 1H), 7.2-7.4 (m, 4H).

11-(1-Benzo[1,3]dioxol-5-ylmethyl-piperidin-4-ylidene)-6,11-dihydro-dibenzo[b,e]oxepine-3-carboxylicacid diethylamide Hydrochloride, 9c

Following Procedure 9, substituting benzo[1,3]dioxole-5-carbaldehyde for3-furaldehyde and compound 8c for compound 10a, the title compound wasprepared. The crude product was converted into its HCl salt usingethereal hydrogen chloride. MS m/z (MH⁺) 511.34; ¹H NMR 300 MHz (CDCl₃)δ 1.2 (br d, 6H), 2.3-2.7 (m, 12H), 2.4-3.1 (m, 6H), 4.05 (s, 2H), 4.8(d, 1H),) 5.7 (d, 1H) 6.8-7.4 (m, 10H).

11-(1-Phenylethylpiperidin-4-ylidene)-6,11-dihydro-dibenzo[b,e]oxepine-3-carboxylicdiethylamide Hydrochloride 10c

Following Procedure 9, compound 8c was converted to the title compound,substituting phenylacetaldehyde for 3-furaldehyde, and compound 8c forcompound 10a. The crude product was converted into its HCl salt usingethereal hydrogen chloride. MS m/z (MH⁺) 481.35; ¹H NMR 300 MHz (CDCl₃)δ 1.2 (br d, 6H), 2.3-2.7 (m, 12H), 2.4-3.7 (m, 16H), 4.8 (d, 1H), 5.7(d, 1H), 6.8-7.4 (m, 12H).

11-Oxo-6,11-dihydro-dibenzo[b,e]oxepine-3-carboxylic acid ethylamide,11c

Following an adaptation of Procedure 6, substituting ethylamine fordiethylamine, compound 4c was converted into its monoethyl amide.

11-(8-Phenethyl-8-aza-bicyclo[3.2.1]oct-3-ylidene)-6,11-dihydro-dibenzo[b,e]oxepine-3-carboxylicacid ethylamide, 12c

A sample of compound 11c was converted to the title compound followingProcedure 7, substituting compound 11c for compound 6a and substitutingN-phenethyl-4-tropinone for N-carbethoxynortropinone. The title compoundwas isolated as its TFA salt. MS m/z 479.1 (M+1); ¹H NMR 300 MHz(DMSO-d₆) δ 1.1 (t, 3H), 1.35 (m, 1H), 1.8 (m, 1H), 2.2 (m, 2H), 2.5 (m,2H), 2.8 (dd, 2H), 3.1 (m, 2H), 3.3 (m, 2H), 3.75 (m, 2H), 4.1 (m, 2H),5.0 (m, 1H), 5.7 (m, 1H), 7.0-7.7 (m, 11H), 8.4 (7, 1H), 10.0 (br s,1H).

11-(1-Allyl-piperidin-4-ylidene)-6,11-dihydro-dibenzo[b,e]oxepine-3-carboxylicacid diethylamide, 13c

Following Procedure 11, substituting compound 8c for compound 10a, thetitle compound was prepared. MS m/z (MH⁺) 417.33; ¹H NMR 300 MHz (CDCl₃)δ 1.2 (br d, 6H), 2.4 (m, 1H), 2.6 (m, 1H), 2.8 (m, 2H), 3.0-3.8 (m,10H), 4.8 (d, 1H), 5.3-5.7 (m, 3H), 6.2 (m, 1H), 6.8-7.4 (m, 7H).

Example D Grignard Method

Procedure 183-Bromo-11-(1-methyl-piperidin-4-yl)-6,11-dihydro-dibenzo[b,e]oxepin-11-ol,1d

A sample of 4-chloro-1-methyl-piperidine hydrochloride salt was basifiedwith KOH and extracted with CH₂Cl₂. The organic phase was dried overmagnesium sulfate and concentrated under vacuum. The crude product wasdistilled from CaH₂ at 50° C. at 1 mmHg.

Magnesium turnings (3.42 g, 143 mmol) were suspended in 15 mL of dry THFunder nitrogen. To this was added CH₂Br₂ (1.25 mL, 14.5 mmol) and avigorous reaction was observed. The reaction was heated to reflux, and4-chloro-1-methyl-piperidine (21 mL, 128 mmol) was added. The reactionwas refluxed for 1 h. The reaction was allowed to cool, and thesupernatant was transferred via cannula to a stirring solution ofcompound 2c (8 g, 128 mmol) in THF at room temperature. The slurry wasrinsed with 2×20 mL THF and the supernatant was transferred. At thattime, all of the starting ketone had been consumed. To the reaction wasadded saturated sodium bicarbonate, and the mixture was extracted withethyl acetate. The combined organics were dried over magnesium sulfate,filtered, and concentrated. The crude product Compound 1d was usedwithout further purification. MS m/z (MH⁺) 388.14.

Procedure 194-(3-Bromo-6H-dibenzo[b,e]oxepin-11-ylidene)-1-methyl-piperidine, 2d

A solution of compound 1d (9.53 g, 24.6 mmol) in 50 mL formic acid washeated to reflux for 5 h. The reaction was concentrated, diluted withethyl acetate, and washed with 3 N HCl, then with 3 N KOH to givecompound 2d (9.0 g). MS m/z (MH⁺) 370.0.

11-(1-Methyl-piperidin-4-ylidene)-6,11-dihydro-dibenzo[b,e]oxepine-3-carboxylicacid methyl ester, 3d

The title compound 3d was synthesized using an adaptation of Procedure4. MS m/z (MH⁺) 350.2.

11-(1-Methyl-piperidin-4-ylidene)-6,11-dihydro-dibenzo[b,e]oxepine-3-carboxylicacid, 4d

The title compound 4d was synthesized from compound 3d using anadaptation of Procedure 5.

11-(1-Methyl-piperidin-4-ylidene)-6,11-dihydro-dibenzo[b,e]oxepine-3-carboxylicacid ethylamide, 5d

The title compound was synthesized from compound 4d using an adaptationof Procedure 6, substituting ethylamine for diethylamine. MS m/z (MH⁺)363.0.

4-(3-Ethylcarbamoyl-6H-dibenzo[b,e]oxepin-11-ylidene)-piperidine-1-carboxylicacid 2,2,2-trichloro-ethyl ester, 6d

The title compound was synthesized from compound 5d using an adaptationof Procedure 16. MS m/z (MH⁺) 523.0.

11-Piperidin-4-ylidene-6,11-dihydro-dibenzo[b,e]oxepine-3-carboxylicacid ethylamide, 7d

Compound 6d was converted to the title compound using an adaptation ofProcedure 17. MS m/z (MH⁺) 349.0.

Following Procedure 9, compound 7d was converted into the followingseries of compounds, substituting the appropriate aldehyde for3-furaldehyde:

MS m/z Ex # Aldehyde R³ (MH⁺)  8d 4-Methyl-but-3-enal 2-Methyl-but-2-ene417.1  9d Thiophene-2-carbaldehyde Thiophen-2-yl methyl 445.1 10d2-Methyl-propenal 2-Methyl-allyl 403.1 11d CyclopropanecarbaldehydeCyclopropylmethyl 403.1 12d 2-Pyridinecarboxaldehyde Pyridin-2-yl methyl440.1 13d 1H-Imidazole-4-carbaldehyde 1H-Imidazol-4-yl methyl 429.1 14d4-Hydroxy-3-methoxy- 4-Hydroxy-3-methoxy- 485.1 benzaldehydephenylmethyl 15d Phenyl-acetaldehyde Phenethyl 453.2

11-(1-Allyl-piperidin-4-ylidene)-6,11-dihydro-dibenzo[b,e]oxepine-3-carboxylicacid ethylamide, 16d

Following Procedure 11, substituting compound 7d for compound 10a, thetitle compound 16d was prepared. MS m/z (MH⁺) 389.1.

Example E McMurry on Bromide

4-(3-Bromo-xanthen-9-ylidene)-1-methyl-piperidine, 1e

Compound 3a was converted into the title compound 1e following anadaptation of Procedure 7, substituting compound 3a for compound 6a andsubstituting N-Methyl-piperidone for N-carbethoxynortropinone. MS m/z(MH⁺) 356.

9-(1-Methyl-piperidin-4-ylidene)-9H-xanthene-3-carboxylic acid methylester, 2e

Compound 1e was converted into its methyl ester 2e by an adaptation ofProcedure 4. MS m/z (MH⁺) 336.1.

9-(1-Methyl-piperidin-4-ylidene)-9H-xanthene-3-carboxylic acid, 3e

Compound 2e was converted into the corresponding carboxylic acidcompound 3e by an adaptation of Procedure 5. MS m/z (MH⁺) 321.1.

9-(1-Methyl-piperidin-4-ylidene)-9H-xanthene-3-carboxylic aciddiethylamide, 7b

Compound 3e was converted into the title diethylamide, compound 7b,using an adaptation of Procedure 6.

Example F

N-[4-(5-Bromo-2-cyano-phenoxy)-phenyl]-acetamide, 1f

Compound 1f was synthesized by that described for the synthesis ofcompound 1a in Procedure 1, substituting N-(4-hydroxyphenyl)-acetamidefor phenol.

2-(4-Amino-phenoxy)-4-bromo-benzoic acid, 2f

Using the method described in Procedure 2, substituting compound 1f forcompound 1a, the title compound 2f was synthesized in quantitativeyield. CIMS m/z=307 (M+1).

Procedure 20 2-(4-Acetylamino-phenoxy)-4-bromo-benzoic acid, 3f

Compound 2f (500 mg, 1.6 mmol) in 10 mL of THF was treated with acetylchloride (0.15 mL, 2.08 mmol) and triethylamine (0.22 mL, 2.08 mmol).After stirring for 2.5 h the solid was collected. The filtrate wasevaporated in vacuo to give 0.48 g of Compound 3f. MS m/z=331 (M+1).

N-(6-Bromo-9-oxo-9H-xanthen-2-yl)-acetamide, 4f

The title compound was synthesized using an adaptation of Procedure 3,substituting compound 3f for compound 2a.

7-Acetylamino-9-oxo-9H-xanthene-3-carboxylic acid methyl ester, 5f

The title compound was synthesized using an adaptation of Procedure 4,substituting compound 4f for compound 3a.

7-Acetylamino-9-oxo-9H-xanthene-3-carboxylic acid, 6f

The title compound was synthesized using an adaptation of Procedure 5,substituting compound 5f for compound 4a.

Procedure 21 7-Acetylamino-9-oxo-9H-xanthene-3-carboxylic aciddiethylamide, 7f

Compound 6f (2 g, 6.7 mmol) in 35 mL of DMF was treated with HATU (2.5g, 6.7 mmol), diethylamine (0.2 mL, 8.7 mmol), and diisopropylethylamine(4.75 mL, 26.8 mmol). After stirring for 3 h the reaction was pouredinto water and the solid was collected to give the product, compound 7f.The filtrate was extracted with diethyl ether/THF (1:1). The combinedorganic phases were washed with water, brine, and dried over magnesiumsulfate. The solvent was evaporated in vacuo and combined with the abovesolid to give 1.5 g total of compound 7f. MS m/z=353 (M+1).

7-Acetylamino-9-hydroxy-9-(1-methyl-piperidin-4-yl)-9H-xanthene-3-carboxylicacid diethylamide, 8f

The title compound was synthesized by an adaptation of Procedure 18,substituting compound 7f for compound 2c.

Procedure 227-Acetylamino-9-(1-methyl-piperidin-4-ylidene)-9H-xanthene-3-carboxylicacid diethylamide, 9f

Into a flask was placed compound 8f (0.3 g, 0.66 mmol) andtrifluoromethanesulfonic acid (2 mL). After heating on a steam bath for1 h the reaction was poured into 3 N NaOH and ice. The aqueous solutionwas extracted with CH₂Cl₂ and dried over sodium sulfate. The solvent wasevaporated in vacuo and the resulting residue was passed through a flashcolumn (silica gel; 90:10:1 CH₂Cl₂:CH₃OH:NH₄OH) to give 0.01 g ofcompound 9f. MS m/z=435 (M+1).

7-Acetylamino-9-piperidin-4-ylidene-9H-xanthene-3-carboxylic aciddiethylamide, 10f

Compound 10f was synthesized by an adaptation of Procedure 7,substituting compound 7f for compound 6a, and substitutingN-Boc-piperidone for N-carbethoxynortropinone. MS m/z=420.3 (M+1).

Example G Procedure 23 9-Piperidin-4-yl-9H-xanthene-3-carboxylic aciddiethylamide, Hydrochloride

A sample of the hydrochloride salt of compound 1b (0.19 g, 0.52 mmol)was dissolved in 3 mL of CHCl₃, treated with iodotrimethylsilane (0.15mL), sealed in a pressure tube and heated on a steam bath for 2 h. Themixture was cooled and the tube was opened. A second portion ofiodotrimethylsilane (0.15 mL) was added, the tube was recapped, and thevessel heated an additional 3 h on the steam bath. The reaction wascooled and 3 mL of MeOH was added. The reaction mixture was partitionedbetween CH₂Cl₂ and NaOH solution. The organic layer was washed withsodium dithionite solution. The solvent was evaporated and the residueflash chromatographed with 90% CH₂Cl₂: 10% 2N NH₃ in MeOH to give thetitle compound. A hydrochloride salt was prepared from Et₂O/HCl. MS m/z(MH⁺) 364.9; ¹H NMR 300 MHz (CDCl₃) δ 1.2 (br s, 6H), 1.5 (m, 2H), 1.7(m, 2H), 2.8 (m, 2H), 3.2-3.4 (m, 4H), 3.5 (br s, 2H), 3.7 (d, 1H),7.1-7.3 (m, 7H).

9-(1-Methylpiperidin-4-yl)-9H-xanthene-3-carboxylic acid diethylamide,Hydrochloride

Following the protocol of Procedure 23 and substituting thehydrochloride salt of compound 7b for the hydrochloride salt of compound1b, the title compound was obtained. MS m/z (MH⁺) 364.9; ¹H NMR 300 MHz(CDCl₃) δ 1.2 (br s, 6H), 1.4 (m, 1H), 1.7 (m, 2H), 2.05 (q, 2H), 2.7(s, 3H), 3.1-3.5 (m, 6H), 3.7 (d, 1H), 7.1-7.3 (m, 7H), 12.2 (s, 1H).

Example H

Procedure 24 4-Bromo-2-phenylsulfanyl-benzonitrile, 1 h

Sodium hydride (2.40 g, 60 mmol) (60% by wt) was weighed into a flaskand washed with several hexane rinsings. The hexanes were decanted anddiscarded and 20 mL DMF was added to the flask. A DMF-solution ofbenzenethiol (5.1 mL, 50 mmol in 50 mL DMF) was added dropwise to theNaH mixture and stirred at room temperature. To4-bromo-2-fluoro-benzonitrile (10.0 g, 50 mmol) in 40 mL DMF) was addedbenzenethiophenoxide (described above), dropwise, over 30 minutes. Uponcomplete addition, the reaction was stirred at room temperature for 20min. At that time, the mixture was poured into cold 1 N NaOH. Aprecipitate formed and was collected by vacuum filtration to give 14.0 g(48.4 mmol) of Compound 1h.

4-Bromo-2-phenylsulfanyl-benzoic acid, 2h

Following Procedure 2, substituting compound 1h for compound 1a,Compound 2h was obtained.

3-Bromo-thioxanthen-9-one, 3h

Following Procedure 3, substituting Compound 2h for compound 2a,compound 3h was obtained.

9-Oxo-9H-thioxanthene-3-carboxylic acid methyl ester, 4h

Following Procedure 4, substituting compound 3h for compound 3a,compound 4h was obtained.

9-Oxo-9H-thioxanthene-3-carboxylic acid, 5h

Following Procedure 5, substituting compound 4h for compound 4a,Compound 5h was obtained.

9-Oxo-9H-thioxanthene-3-carboxylic acid diethylamide, 6h

Following Procedure 6, substituting compound 5h for compound 5a,Compound 6h was obtained.

9-Oxo-9H-thioxanthene-3-carboxylic acid ethylamide, 7h

Following Procedure 6, substituting ethylamine for diethylamine, andcompound 5h for compound 5a Compound 7h was obtained.

3-(3-Diethylcarbamoyl-thioxanthen-9-ylidene)-8-aza-bicyclo[3.2.1]octane-8-carboxylicacid ethyl ester, 8h

Following the procedure described in Procedure 7, substituting compound6h for compound 6a, Compound 8c was obtained. MS m/z=477.1 (MH⁺).

9-(8-Aza-bicyclo[3.2.1]oct-3-ylidene)-9H-thioxanthene-3-carboxylic aciddiethylamide, 9h

Following Procedure 8, substituting compound 8h for compound 8a,Compound 9h was obtained. The product was then converted into itsfumarate salt. MS m/z (MH⁺)=405.4. ¹H NMR 300 MHz (CDCl₃) δ 1.05-1.3 (m,6H), 1.40 (m, 2H), 1.9 (m, 2H), 2.75 (m, 2H), 3.1 (m, 2H), 3.3 (m, 2H),3.6 (m, 2H), 3.90 (br s, 2H), 7.2 (m, 5H), 7.5 (m, 2H).

9-(8-Benzo[1,3]dioxol-5-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-ylidene)-9H-thioxanthene-3-carboxylicacid diethylamide, 10h

Following Procedure 9, substituting compound 9h for compound 10a, andsubstituting piperonal for 3-furaldehyde, Compound 10h was obtained. Theproduct was then converted into its fumarate salt. MS m/z (MH⁺)=439.4.Fumarate salt: ¹H NMR 300 MHz (DMSO-d₆) δ 0.9-1.2 (m, 8H), 1.90 (m, 2H),2.55 (m, 2H), 2.95 (m, 2H), 3.19 (m, 2H), 3.4 (m, 4H), 3.80 (br s, 2H),6.05 (s, 2H), 6.65 (s, 2H), 6.9 (m, 2H), 7.2 (s, 1H), 7.35 (m, 5H), 7.6(m, 2H).

9-(R³-8-aza-bicyclo[3.2.1]oct-3-ylidene)-9H-thioxanthene-3-carboxylicacid diethylamide, 11h-12h

Following Procedure 9, substituting the appropriate aldehyde for3-furancarboxaldehyde, the following compounds were prepared:

MS m/z Ex # Aldehyde R³ (MH⁺) 11h Cyclopropane Cyclopropylmethyl 459.7carboxaldehyde 12h 3-(Methylthio)-3- Methanesulfanyl-propyl 493.5propionaldehyde

9-[8-(2Hydroxy-ethyl)-8-aza-bicyclo[3.2.1]oct-3-ylidene]-9H-thioxanthene-3-carboxylicacid diethylamide, 13h

Following Procedure 11, substituting compound 9h for compound 10a, andsubstituting 2-iodoethanol for allyl bromide, compound 13h was obtained.MS m/z (MH⁺)=449.2. ¹H NMR 300 MHz (CDCl₃) δ 1.05-1.4 (m, 8H), 1.8 (m,2H), 2.6-2.8 (m, 4H), 3.0 (m, 2H), 3.5 (m, 4H), 3.80 (m, 2H), 4.8 (br s,1H), 7.2 (m, 5H), 7.5 (m, 2H).

Procedure 25

The (+) and (−) enantiomers of compound 24 (compounds 52 and 53), inTable 1 herein were separated on a preparative chiralpak AD column (500grams of 20 micron material, 5×41 cm) using hexane/methanol/ethanol(50/25/25) as eluent. The analytes were monitored using a wavelength of220 nm. For analytical work, the same column material was used(chiralpak AD, 4.6×50 mm), and the same solvents, but in a 80/10/10proportion.

The (+) and (−) enantiomers of compound 54 (compounds 55 and 56), inTable 1 herein were separated on a preparative Chiralpak AD column (500grams of 20 micron material, 50×41 cm) using heptane/ethanol (85/15) aseluent. The analytes were monitored using a wavelength of 220 nm.

Example I

Procedure 26(2,4-Difluoro-phenyl)-(2-hydroxy-4-methoxy-phenyl)-methanone, 3i

Aluminum chloride (2.03 g, 15.2 mmol) was added in portions to asolution of 1,3-dimethoxybenzene (1.86 mL, 15.2 mmol) and2,4-difluorobenzoyl chloride (1.86 mL, 15.2 mmol) in 1,2-dichloroethaneat 0° C. The mixture was allowed to warm to rt over 3 h then heated atreflux for 6 h. The resultant mixture was allowed to cool to rt, thenpoured into a mixture of ice (˜100 g) and concentrated hydrochloric acid(˜20 mL). The organic layer was separated. The aqueous solution wasstirred at ambient temperature overnight, and extracted withdichloromethane. The organic layers were washed with aqueous sodiumbicarbonate and dried over magnesium sulfate. The solvents wereevaporated in vacuo to give crude product. A portion of the product waspurified by flash chromatography on silica gel, using a gradient of1%-10% EtOAc/heptane as the eluent to give the title compound 3i (1.8g). MS: m/z 264.9 (MH⁺). ¹H NMR (CDCl₃): δ 3.90 (s, 3H), 6.42 (d of d,1H, J=9.0 and 2.5 Hz), 6.50 (d, 1H, J=2.5 Hz), 6.91-7.04 (m, 2H),7.27-7.29 (m, 1H), 7.44-7.50 (m, 1H) and 12.44 (s, 1H).

Procedure 27 3-Fluoro-6-methoxy-xanthen-9-one, 41

A mixture of potassium carbonate (2.13 g, 15.4 mmol) and(2,4-difluoro-phenyl)-(2-hydroxy-4-methoxy-phenyl)-methanone (3.4 g,12.9 mmol) in N,N-dimethylformamide (50 mL) was heated at 100° C. for 2h. The mixture was cooled and poured into water (˜150 mL). A solid wascollected by filtration, washed with water, and dried in vacuo to givethe title compound (2.8 g), which was used without purification in thesubsequent step. MS: m/z 244.9 (MH⁺). ¹H NMR (CDCl₃): δ 3.94 (s, 1H),6.88 (d, 1H, J=2.4 Hz), 6.96 (d of d, 1H, J=2.4 & 8.9 Hz), 7.07 (m, 2H),8.24 (d, 1H, 8.9 Hz) and 8.34 (d of d, 1H, J=6.5 & 8.8 Hz).

Procedure 28 6-Methoxy-9-oxo-9H-xanthene-3-carbonitrile, 51

A mixture of finely ground sodium cyanide (1.3 g, 26.5 mmol) and3-fluoro-6-methoxy-xanthen-9-one (2.3 g, 9.42 mmol) inN,N-dimethylformamide (30 mL) was heated at 100° C. for 4 hours. Sodiumcyanide (0.7 g, 14.3 mmol) was added and heating continued an additionalhour. The mixture was allowed to cool to room temperature, then pouredinto ice water (˜150 mL). The product was collected by filtration,washed with water and air dried to give Compound 5i, 1.42 g (60%). MS:m/z 251.9 (MH⁺). ¹H NMR (CDCl₃): δ 3.96 (s, 3H), 6.91 (d, 1H, J=2.3 Hz),7.00 (d of d, 1H, J=2.3 & 8.9 Hz), 7.61 (d of d, 1H, J=1 & 8.1 Hz), 7.79(d, 1H, J=1 Hz), 8.24 (d, 1H, J=8.9 Hz) and 8.42 (d, 1 H, J=8.1 Hz).

6-Methoxy-9-oxo-9H-xanthene-3-carboxylic acid, 61

Using the method described in Procedure 2, substituting compound 51 forcompound 1a, the title compound was prepared (0.75 g). MS: m/z 270.9(MH⁺). ¹H NMR (DMSO-d₆): δ 3.95 (s, 3H), 7.06 (d of d, 1H, 2.4 & 8.9Hz), 7.17 (d, 1H, J=2.4 Hz), 7.94 (d of d, 1H, J=1.4 & 8.2 Hz), 8.03 (d,1H, J=1.4 Hz), 8.10 (d, 1H, J=8.9 Hz), 8.24 (d, 1H, J=8.2 Hz) and 13.65(br s, 1H).

Procedure 29 6-Methoxy-9-oxo-9H-xanthene-3-carboxylic acid diethylamide,71

A mixture of compound 6i (0.707 g, 2.62 mmol) andO-benzotriazol-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU, 1.05 g, 2.74 mmol) in N,N-dimethylformamide (10 mL) was treatedwith N,N-diisopropylethylamine (DIEA, 0.685 mL, 3.92 mmol) and allowedto stir at rt for 15 min. Diethylamine (0.541 mL, 5.23 mL) was added andthe resultant mixture was stirred for 2 h. The mixture was poured intoice water. A solid was collected by filtration, washed with water andair dried to give the title compound (0.445 g). MS: m/z 326.0 (MH⁺). ¹HNMR (DMSO-d₆): δ 1.07 (br t, 3H), 1.19 (br t, 3H), 3.20 (br q, 2H), 3.48(br t, 2H), 3.95 (s, 3H), 7.08 (m, 1H), 7.17 (d, 1H, J=2.1 Hz), 7.40 (dof d, 1H, J=1.3 & 8.1 Hz), 7.59 (d, 1H, J=1.2 Hz), 8.12 (d of d, 1H,J=1.3 & 8.9 Hz) and 8.21 (d, 1H, J=8.1 Hz).

Procedure 309-(8-Aza-bicyclo[3.2.1]oct-3-ylidene)-6-methoxy-9H-xanthene-3-carboxylicacid diethylamide, 81

A suspension of zinc powder (0.626 g, 9.60 mmol) in THF (20 mL), at 0°C. was treated with titanium(IV)chloride (0.525 mL, 4.79 mmol), bydropwise addition. The resultant mixture was heated at reflux for 2 h.The resultant solution was cooled to room temperature, and3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester(0.270 g, 1.20 mmol) and compound 7i (0.390, 1.20 mmol) were added andthe solution was heated at reflux for 2 h. Potassium sodium tartrate(2.98 g, 10 56 mmol), dissolved in a minimal amount of water, was addedto the reaction mixture and allowed to stir at ambient temperatureovernight. The inorganic solids were removed by filtration and washedgenerously with THF. The solvent was evaporated in vacuo, and theresidue was partitioned between dichloromethane and 10% aqueous ammoniumhydroxide. The organic layer was separated and dried over sodiumsulfate. The solvent was evaporated in vacuo. The residue was taken upin DMSO and purified by reverse phase preparative HPLC(C₁₈), using agradient of acetonitrile (10% to 90%) in water with TFA (0.1%), to givethe title compound as its trifluoroacetic acid salt (0.50 g). MS: m/z419.1 (MH⁺). ¹H NMR (DMSO-d₆): δ 1.0-1.2 (br m, 6H), 1.32 (br d, 2H),1.78 (br m, 2H), 2.85-3.02 (br m, 4H), 3.2-3.55 (br m, 4H), 3.80 (s,3H), 3.96-4.05 (br s, 2H), 6.81 (d of d, 1H, J=2.5 & 8.6), 6.88 (d, 1H,J=2.5 Hz), 7.15 (d of d, 1H, J=1.4 & 7.8 Hz), 7.20 (d, 1H, J=1.4 Hz),7.31 (d, 1H, J=8.6 Hz), 7.41 (d, 1H, J=7.8 hZ), 8.81 br s, 1H) and 9.12(br d, 1H).

Procedure 319-(8-Aza-bicyclo[3.2.1]oct-3-ylidene)-6-hydroxy-9H-xanthene-3-carboxylicacid diethylamide, 9i

A 1.0 M solution of boron tribromide in dichloromethane (2.14 mL, 2.14mmol) was added to a solution of the trifluoroacetic acid salt of9-(8-aza-bicyclo[3.2.1]oct-3-ylidene)-6-methoxy-9H-xanthene-3-carboxylicacid diethylamide (0.285 g, 0.535 mmol) in dichloromethane (10 mL) at 0°C. The resultant mixture was stirred at room temperature for 2 h. Themixture was cooled to 0° C., and treated with 10% aqueous ammoniumhydroxide (˜20 mL). The organic layer was separated and the aqueouslayer was extracted with dichloromethane. The combined organic layerswere washed with brine and dried over sodium sulfate. The solvent wasevaporated in vacuo, and the residues was dissolved in DMSO and appliedto reverse phase C₁₈ column for purification via HPLC, using a gradientof acetonitrile (10% to 90%) in water with trifluoroacetic acid (0.1%)as the eluant. Fractions containing the title compound were combined andfurther purified via reverse phase HPLC to give the purified titlecompound (0.035 g). MS: m/z 405.1 (MH⁺). ¹H NMR (DMSO-d₆): δ 1.0-1.2 (brm, 6H), 1.29 (d, 12H, J=8.1 Hz), 1.7-1.8 (br m, 2H), 2.8-3.0 (br m, 4H),3.1-3.5 (br m, 4H), 3.99 (br s, 2H), 6.63-6.65 (m, 2H), 7.13 (d, 1 H,J=7.9 Hz), 7.18-7.21 (m, 3H), 7.41 (d, 1H, J=7.9 Hz), 8.70 (br s, 1H),9.01 br d, 1H) and 9.93 (br s 1H).

Example J

Procedure 32 2-(2-Bromo-phenoxy)-terephthalic acid dimethyl ester, 3j

A mixture of 2-fluoro-terephthalic acid dimethyl ester 2j (10 g, 47.1mmol), 2-bromophenol 1j (6.0 mL, 51.8 mmol) and potassium carbonate(7.16 g, 51.8 mmol) in N,N-dimethylformamide (100 mL) was heated at 100°C. for 36 h. The mixture was allowed to cool to rt, then poured intocold dilute hydrochloric acid (0.5 N, 350 mL). The product was extractedinto EtOAc, washed with water (4×) and brine (1×) and dried overmagnesium sulfate. The solvent was evaporated in vacuo, and the residuewas purified by flash chromatography on silica gel using dichloromethaneas the eluant. The crude product was isolated (10.5 g) and used withoutfurther purification in the subsequent reaction. MS: m/z 365 (MH⁺).

Procedure 33 5-Bromo-9-oxo-9H-xanthene-3-carboxylic acid, 5j (via 4j)

2-(2-Bromo-phenoxy)-terephthalic acid dimethyl ester (10 g) was addeddropwise to hot (100° C.) polyphosphoric acid (280 g) over 5 min. Thesolution was heat at 155° C. for 2 h at which point the heating wascontinued at 180° C. for an additional 2 h. The solution was mixed witha large volume of ice water. The resultant solids were collected byfiltration, washed with water and purified by flash chromatography onsilica gel, using a gradient of methanol (1% to 10%) in dichloromethanewith acetic acid (0.1%) to give compound 4j (1.25 g). The acid compound5j was isolated from the latter fractions (3.52 g).

A solution of the ester compound 4j (1.25 g, 3.75 mmol) and 3 N sodiumhydroxide (1.37 mL, 4.12 mmol) in MeOH (30 mL) was heated at reflux for2 h. The solution was cooled to rt and made acidic with 2 N hydrochloricacid (˜2.5 mL). The mixture was concentrated in vacuo, and then dilutedwith water. The resultant solid was collected by filtration, washed withwater and air dried to yield an additional 1.08 g of compound 5j. MS:m/z 318.7 (MH⁺). ¹H NMR (DMSO-d₆): δ 7.43 (t, 1H, J=7.8 Hz), 7.98 (d ofd, 1H, J=1.4 & 8.2), 8.09 (d, 1 H, J=1.3 Hz), 8.17-8.23 (m, 2H) and 8.28(d, 1H, J=8.2 Hz).

5-Bromo-9-oxo-9H-xanthene-3-carboxylic acid diethylamide, 6j

Using the method described in Procedure 29, substituting compound 5j forcompound 6i, the title compound was prepared. Subsequent purification byflash chromatography, using dichloromethane as the eluant gave Compound6j (4.4 g). MS: m/z 373.8 (MH⁺). ¹H NMR (CDCl₃): δ 1.16 (t, 3H, J=6.8Hz), 1.30 (t, 3H, J=6.8 Hz), 3.28 (q, 2H, J=6.8 Hz), 3.60 (q, 2H, J=6.8Hz), 7.30 (d, 1H, J=7.9 Hz), 7.40 (d of d, 1H, J=1.4 & 8.0 Hz), 7.64 (d,1H, J=1.4 Hz), 7.98 (d of d, 1H, J=1.6 & 7.9 Hz), 8.30 (d of d, 1H,J=1.6 & 8.0 Hz) and 8.36 (d, 1H, J=8.1 Hz).

Procedure 349-(8-Aza-bicyclo[3.2.1]oct-3-ylidene)-5-bromo-9H-xanthene-3-carboxylicacid diethylamide, 7j

A suspension of zinc powder (5.59 g, 85.5 mmol) in tetrahydrofuran (THF,100 mL) at 0° C., was treated with titanium(IV)chloride (4.69 mL, 42.8mmol) by dropwise addition. The resultant mixture was heated at refluxfor 2 h. The resultant solution was cooled to 0° C.3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (2.4g, 10.7 mmol) and 5-bromo-9-oxo-9H-xanthene-3-carboxylic aciddiethylamide (4.0 g, 10.7 mmol) were added and the solution was heatedat reflux for 4 h. Potassium sodium tartrate tetrahydrate (30 g, 106mmol) was added to the reaction mixture and allowed to stir at ambienttemperature overnight. The inorganic solids were removed by filtrationand washed successively with THF, EtOAc and dichloromethane. The solventwas evaporated in vacuo. Purification by flash chromatography using agradient 1% to 10% methanol (with ammonia, 2 N) in dichloromethane asthe eluent gave Compound 7j (3.65 g). Crude product was purified byreverse phase preparative HPLC, using a gradient of acetonitrile (10% to90%) in water with trifluoroacetic acid (0.1%), to give thetrifluoroacetic acid salt of compound 7j. MS: m/z 467.0 (MH⁺). ¹H NMR(DMSO-d₆): δ 1.0-1.2 (br m, 6 H), 1.32 (d, 2H, J=7.9 Hz), 1.75-1.85 (brm, 2H), 2.85-3.10 (m, 4H), 3.15-3.50 (br m, 4H), 4.01 br s, 2H),7.15-7.26 (m, 3H), 7.42 (d, 1H, J=6.7 Hz), 7.49 (d, 1H, J=7.9 Hz), 7.66(d, 1H, J=7.9 Hz), 8.81 (br s, 1H) and 9.12 br d, 1H).

Procedure 359-(8-Aza-bicyclo[3.2.1]oct-3-ylidene)-5-phenyl-9H-xanthene-3-carboxylicacid diethylamide, 8j

A mixture of9-(8-aza-bicyclo[3.2.1]oct-3-ylidene)-5-bromo-9H-xanthene-3-carboxylicacid diethylamide (0.170, 0.363 mmol), phenylboronic acid (0.049 g, 0.40mmol) and cesium carbonate (0.236 g, 0.726 mmol) in dioxane (4 mL) andethanol (1 mL) was treated withdichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (13 mg), and the resulting mixture was heated atreflux for 2 h. The reaction mixture was cooled to room temperature, andthe inorganics removed by filtration and washed successively withdioxane, ethanol and dichloromethane. The solvents were evaporated invacuo. The residue was purified by reverse phase (C₁₈) preparative HPLC,using a gradient of acetonitrile (10% to 90%) in water withtrifluoroacetate (0.1%) as the eluant to give the title compound (0.153g) as a colorless solid. MS: m/z 465.3 (MH⁺). ¹H NMR (DMSO-d₆): δ1.05-1.20 (br m, 6H0, 1.31 d, 2H, J=8.2 Hz), 1.75-1.85 (br m, 2H),2.90-3.10 (m, 4H), 3.15-3.50 (br m, 4H), 4.03 br s, 2H), 7.10 (d, 1H,J=1.5 Hz), 7.20 (d of d, 1H, J=1.5 & 7.9 Hz), 7.32 (t, 1H, J=7.5 Hz),7.40-7.63 (m, 8H), 8.83 (br s, 1H0 and 9.16 (br d, 1H).

9-(8-Aza-bicyclo[3.2.1]oct-3-ylidene)-5-methoxy-9H-xanthene-3-carboxylicacid diethylamide

The title compound was prepared following Example J and substituting2-methoxyphenol for 2-bromophenol in Procedure 32. MS: m/z 419.1 (MH⁺).¹H NMR (DMSO-d₆): δ 1.0-1.2 (m, 6H), 1.29 (br m, 1H), 1.73-1.82 (m, 2H),2.87-3.15 (m, 4H), 3.22 (br m, 2H), 3.42 (br m, 2H), 3.88 (s, 3H), 4.00(br s, 2H), 6.95 (d, J=7.5 Hz, 1H), 7.07-7.19 (m, 3H), 7.22 (d, J=1.5Hz, 1H), 7.44 (d, J=7.9 Hz, 1H), 8.77 (br s, 1H) and 9.08 (br s, 1H).

9-(8-Aza-bicyclo[3.2.1]oct-3-ylidene)-5-hydroxy-9H-xanthene-3-carboxylicacid diethylamide

The title compound was prepared from9-(8-aza-bicyclo[3.2.1]oct-3-ylidene)-5-methoxy-9H-xanthene-3-carboxylicacid diethylamide using an adaptation of Procedure 31. MS: m/z 405.0(MH⁺). ¹H NMR (DMSO-d₆): δ 1.0-1.2 (m, 6H), 1.29 (br m, 1H), 1.73-1.84(m, 2H), 2.95-3.15 (m, 4H), 3.20 (br m, 2H), 3.42 (br m, 2H), 4.00 (brs, 2H), 6.80 (d, J=7.6 Hz, 1H), 6.87 (d, J=7.9 Hz, 1H), 7.02 (t, J=7.9Hz, 1H), 7.15 (d of d, J=1.5 & 7.9 Hz, 1H), 7.25 (d, J=1.5 Hz, 1H), 7.42(d, J=7.9 Hz, 1H), 8.78 (br s, 1H), 9.08 (br s, 1H) and 9.67 (br s, 1H).

9-(8-Aza-bicyclo[3.2.1]oct-3-ylidene)-5-pyridin-4-yl-9H-xanthene-3-carboxylicacid diethylamide

The title compound was prepared following the method described inExample J and substituting pyridin-4-yl boronic acid for phenyl boronicacid in Procedure 35. MS: m/z 466.1 (MH⁺). ¹H NMR (DMSO-d₆): δ 1.0-1.2(m, 6H), 1.32 (br m, 2H), 1.80 (br m, 2H), 2.88-3.42 (br m, 8H), 4.03(br s, 2H), 7.22 (d, J=7.8 Hz, 1H), 7.27 (d, J=1.2 Hz, 1H), 7.42 (t,J=7.6 Hz, 1H), 7.51 (d, J=7.8 Hz, 1H), 7.58 (d, J=7.6 Hz, 1H), 7.63 (d,J=6.8 Hz, 1H), 8.06 (d, J=6.1 Hz, 2H), 8.90 (br m, 3H) and 9.22 (br d,J=9.4 Hz, 1H).

9-(8-Aza-bicyclo[3.2.1]oct-3-ylidene)-5-furan-3-yl-9H-xanthene-3-carboxylicacid diethylamide

The title compound was prepared using the method described in Example J,substituting furan-3-yl boronic acid for phenyl boronic acid inProcedure 35. MS: m/z 455.1 (MH⁺). ¹H NMR (DMSO-d₆): δ 1.0-1.2 (m, 6H),1.30 (br m, 2H), 1.78 (br m, 2H), 2.89-3.05 (m, 4H), 3.20 (br m, 2H),3.44 (br m, 2H), 4.02 (br s, 2H), 7.15 (s, 1H), 7.19 (d, J=7.8 Hz, 1H),7.26-7.31 (m, 2 H), 7.47 (d, J=7.8 Hz, 1H), 7.56 (d, J=1.1 Hz, 1H),7.69-7.72 (m, 1H), 7.82 (s, 1H), 8.59 (s, 1H), 8.83 (br d, 1H) and 9.15(br d, J=9.3 Hz, 1H).

9-(8-Aza-bicyclo[3.2.1]oct-3-ylidene)-5-pyridin-3-yl-9H-xanthene-3-carboxylicacid diethylamide

The title compound was prepared using the method described in Example J,substituting pyridin-3-yl boronic acid for phenyl boronic acid inProcedure 35. MS: m/z 466.1 (MH⁺). ¹H NMR (DMSO-d₆): δ 1.0-1.2 (m, 6H),1.32 (m, 2H), 1.80 (br m, 2H), 2.90-3.02 (m, 4H), 3.20 (br m, 2H), 3.42(br m, 2H), 4.03 (br s, 2H), 7.16 (d, J=1.5 Hz, 1H), 7.20 (d of d, J=1.5& 7.8 Hz, 1H), 7.38 (t, J=7.7 Hz, 1H), 7.49-7.56 (m, 3H), 7.76 (d of d,J=5.0 & 7.9 Hz, 1 H), 8.31 (d, J=8.0 Hz, 1H), 8.74 (d of d, J=1.5 & 5.0Hz, 1H), 8.82 (br s, 1H), 8.95 (s, 1H) and 9.13 (br d, 1H).

9-(8-Aza-bicyclo[3.2.1]oct-3-ylidene)-5-thiophen-3-yl-9H-xanthene-3-carboxylicacid diethylamide

The title compound was prepared using the method described in Example J,substituting thiophen-3-yl boronic acid for phenyl boronic acid inProcedure 35. MS: m/z 471.0 (MH⁺). ¹H NMR (DMSO-d₆): δ 1.0-1.2 (m, 6H),1.31 (m, 2H), 1.78 (br m, 2H), 2.95-3.05 (m, 4H), 3.21 (br m, 2H), 3.43(br m, 2H), 4.02 (br s, 2H), 7.21 (d of d, J=1.5 and 7.8 Hz, 1H), 7.28(t, J=7.6 Hz, 1H), 7.34 (d of d, J=1.4 &7.6 Hz, 1H), 7.38 (d, J=1.4 Hz,1H), 7.48 (d, J=7.8 Hz, 1H), 7.63-7.70 (m, 3H), 8.13 (d of d, J=1.4 &2.8Hz, 1H), 8.80 (br s, 1H) and 9.12 (br d, J=10 Hz, 1H).

Example K 9-(8-Aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-3-carboxylicacid isopropyl-methyl-amide Procedure 36

2-Phenoxy-terephthalic acid dimethyl ester. 2-Iodo-terephthalic aciddimethyl ester (10 g, 31 mmol), phenol (3.23 g, 34 mmol),tetrakis-acetonitrilecopper hexafluorophosphate (2.9 g, 7.8 mmol), andcesium carbonate (10.2 g, 31 mmol) were added to a 1 L 3-neck roundbottom flask equipped with a mechanical stirrer, a reflux condenser andcontaining toluene (350 mL). The reaction was refluxed 5 h undernitrogen with stirring. After cooling, EtOAc (200 mL) was added and themixture was filtered. The filtrate was concentrated to afford the crudetitle compound (9.2 g) that was used without purification.

2-Phenoxy-terephthalic acid dimethyl ester was converted to9-Oxo-9H-xanthene-3-carboxylic acid using an adaptation of Procedure 33.

9-Oxo-9H-xanthene-3-carboxylic acid-N-isopropyl-N-methyl-amide wasprepared from 9-Oxo-9H-xanthene-3-carboxylic acid using an adaptation ofProcedure 29 and substituting N-isopropyl-N-methyl-amine fordiethylamine.

The title compound of Example K was prepared by the method described inProcedure 34, substituting 9-Oxo-9H-xanthene-3-carboxylic acidN-isopropyl-N-methyl-amide for compound 6j. The crude product waspurified by preparative reverse phase chromatography on a C-18 column,eluting with water/acetonitrile/0.1% TFA to yield the product as itstrifluoroacetic acid salt. MS m/z (MH⁺) 389.2; ¹H NMR 300 MHz (DMSO-d₆)δ 1.12 (s, 6H), 1.2-1.3 (m, 2H), 1.79 (m, 2H), 2.82 (m, 3H), 2.95 (q,4H), 4.00 (s, 2H), 7.18-7.21 (m, 1H), 7.24 (d, 2H), 7.30 (d, 1H), 7.36(d, 1H), 7.40-7.46 (m, 2H), 8.77 (m, 1H), 9.09 (d, 1H).

Compounds 1 through 102 in the table, below, were synthesized using theprocedures described above.

TABLE 1 Cpd R₁ R₂ R₃ R₄ R₅ A Y Z  1 Et Et Me H H absent CH₂O O  2 Et EtH H H absent CH₂O O  3 Et Et H H H absent O O  4 Et Et Benzo[1,3] H Habsent CH₂O O dioxol-5-ylmethyl  5 Et Et Phenethyl H H absent CH₂O O  6Et Et Allyl H H absent CH₂O O  7 Et Et Me H H absent O O  8 Et Et AllylH H absent O O  9 Et H Me H H absent CH₂O O 10 Et H1,1,1-Trichloroethoxy H H absent CH₂O O carbonyl 11 Et H H H H absentCH₂O O 12 Et H 2-Methyl-but-2-enyl H H absent CH₂O O 13 Et HThiophen-2-yl methyl H H absent CH₂O O 14 Et H 2-Methyl-allyl H H absentCH₂O O 15 Et H Cyclopropylmethyl H H absent CH₂O O 16 Et HPyridin-2-ylmethyl H H absent CH₂O O 17 Et H 1-H-Imidazol-4-yl H Habsent CH₂O O methyl 18 Et H 4-Hydroxy-3- H H absent CH₂O Omethoxyphenyl-methyl 19 Et H Allyl H H absent CH₂O O 20 Et H Phenethyl HH absent CH₂O O 22 Et Et Phenethyl H H absent O O 23 Et Et Me H H CH₂CH₂O O 24 Et Et H H H CH₂CH₂ O O 25 Et Et Furan-3-ylmethyl H H CH₂CH₂ O O26 Et H Phenethyl H H CH₂CH₂ CH₂O O 27 Et H Phenethyl H H CH₂CH₂ O O 28Et Et Furan-3-ylmethyl H H absent O O 29 Et Et Pyridin-2-ylmethyl H Habsent O O 30 Et Et 2-Hydroxyphenyl- H H absent O O methyl 31 Et EtCarbamimidoyl H H absent O O 32 Et H H H H absent O O 33 Et Et1-Prop-2-ynyl H H absent O O 34 Et Et H Acetyl- H absent O O amino 35 EtEt Hydroxy-ethyl H H absent O O 36 Et Et Phenyliminomethyl H H absent OO 37 Et Et Thioformyl H H absent O O 38 Et Et Allyl H H CH₂CH₂ O O 39 EtEt 2-Methoxy-ethyl H H CH₂CH₂ O O 40 Et Et Methylthioethyl H H CH₂CH₂ OO 41 Et Et Methyl Acetyl- H absent O O amino 42 Et Et H H H absent O O43 Et Et Me H H absent O O 44 Et Et Pyridin-2-ylmethyl H H CH₂CH₂ O O 45Et Et Hydroxyethyl H H CH₂CH₂ O O 46 Et Et 1-H-Imidazol-4-yl H H CH₂CH₂O O methyl 47 Et Et Benzo[1,3] H H CH₂CH₂ S O dioxol-5-ylmethyl 48 Et EtH H H CH₂CH₂ S O 49 Et Et Cyclopropylmethyl H H CH₂CH₂ S O 50 Et EtMethyllthiopropyl H H CH₂CH₂ S O 51 Et Et Hydroxy-ethyl H H CH₂CH₂ S O52 Et Et H H H CH₂CH₂ O O (−) enantiomer 53 Et Et H H H CH₂CH₂ O O (+)enantiomer 54 Et H H H H CH₂CH_(2′) O O 55 Et H H H H CH₂CH₂ O O (−)enantiomer 56 Et H H H H CH₂CH₂ O O (+) enantiomer 57 Me Me H H H CH₂CH₂O O 58 i-Pr H H H H CH₂CH_(2′) O O 59 Me i-Bu H H H CH₂CH₂ O O 60 n-Prn-Pr H H H CH₂CH₂ O O 61 Et Et H H H CH₂CH₂ S O (+) enantiomer 62 Et EtH H H CH₂CH₂ S O (−) enantiomer 63 n-Pr H H H H CH₂CH₂ O O 64 Me H H H HCH₂CH₂ O O 65 H H H H H CH₂CH₂ O O 66 Et Et H 6-methyl H CH₂CH₂ O O 67Et Et H 7-methyl H CH₂CH₂ O O 68 Et Et H 5-methoxy H CH₂CH₂ O O 69 Et EtH 7-Fluoro H CH₂CH₂ O O 70 Et Et H 6-methoxy H CH₂CH₂ O O 71 Et Et1-H-imidazol-5-yl H H CH₂CH₂ O O Enant. A methyl 72 Et Et1-H-imidazol-5-yl H H CH₂CH₂ O O Enant. B methyl 73 Me n-Bu H H HCH₂CH_(2′) O O 74 Et Et 1-H-imidazol-4-yl H H CH₂CH₂ S O methyl 75 Et Et1-H-imidazol-4-yl H H CH₂CH₂ S O methyl 76 Et Et H 6- H CH₂CH_(2′) O Ohydroxy 77 Et Et H 7- H CH₂CH_(2′) O O Methoxy 78 Et H Trifluoromethyl HH CH₂CH_(2′) S O carbonyl 79 Et H Trifluoromethyl H H CH₂CH_(2′) S Ocarbonyl 80 Et H H H H CH₂CH₂ S O 81 Et H H H H CH₂CH₂ S O 82 Et Et H7-hydroxy H CH₂CH₂ O O 83 Et Et H 7-Bromo H CH₂CH₂ O O 84 Et Et H7-phenyl H CH₂CH_(2′) O O 85 Et Et H 7-pyridin- H CH₂CH_(2′) O O 4-yl 86Et Et H 7-furan- H CH₂CH_(2′) O O 3-yl 87 Et Et H 7-benzo H CH₂CH_(2′) OO thiophen- 2-yl 88 Et Et H N-t-Butoxy H CH₂CH_(2′) O O carbonylpyrrol-2-yl 89 Et Et H 7-pyridin- H CH₂CH_(2′) O O 3-yl 90 Et Et H7-thiophen H CH₂CH_(2′) O O 3-yl 91 Et Et H 7-(3,5-dimethyl) HCH₂CH_(2′) O O isoxazol-4-yl 92 Me i-Pr H H H CH₂CH₂ O O 93 Et Et H7-pyrrol-2-yl H CH₂CH_(2′) O O 94 Et Et H 5-bromo H CH₂CH_(2′) O O 95 EtEt H 5-phenyl H CH₂CH_(2′) O O 96 Et Et H 5-pyridin-4-yl H CH₂CH_(2′) OO 97 Et Et H 5-furan-3-yl H CH₂CH_(2′) O O 98 Et Et H 5-quinolin-3-yl HCH₂CH_(2′) O O 99 Et Et H 5-thiophen-3-yl H CH₂CH_(2′) O O 100  Et Et H5-hydroxy H CH₂CH_(2′) O O 101  Et Et H 5-pyridin-3-yl H CH₂CH_(2′) O O102  Et Et H 5-fluoro H CH₂CH_(2′) O O

Biological Examples Rat Brain Mu Opioid Receptor Binding Assay

Procedure: Male, Sprague Dawley (150-250 g, VAF, Charles River,Kingston, N.Y.) are killed by CO₂, and their brains removed and placedimmediately in ice cold Tris HCl buffer (50 mM, pH 7.4). The forebrainsare separated from the remainder of the brain by a coronal transection,beginning dorsally at the colliculi and passing ventrally through themidbrain-pontine junction. After dissection, the forebrains arehomogenized in Tris buffer in a Teflon®-glass homogenizer. Thehomogenate is diluted to a concentration of 1 g of forebrain tissue per80 mL Tris and centrifuged at 39,000×g for 10 min. The pellet isresuspended in the same volume of Tris buffer containing 5 mM MgCl₂ withseveral brief pulses from a Polytron homogenizer. This particulatepreparation is used for the mu-opioid binding assays. Followingincubation with the mu selective peptide ligand ˜0.8 nM [³H]DAMGO at 25°C. for 2.5 h in a 96-well plate with total 1 ml, the plate contents arefiltered through Wallac filtermat B sheets on a Tomtec 96-wellharvester. The filters are rinsed three times with 2 mL of 10 mM HEPES(pH7.4), and dried in a 650 W microwave oven for 1.75 min twice. To eachsample area 2×40 μL of Betaplate Scint scintillation fluid (LKB) isadded and analyzed on a LKB (Wallac) 1205 BetaPlate liquid scintillationcounter.

Analysis: The data from the scintillation counter are used to calculateeither the % inhibition compared to control binding (when only a singleconcentration of test compound is evaluated) or a K_(i) value (when arange of concentrations is tested). % inhibition is calculated as:[(total dpm−test compound dpm)/(total dpm−nonspecific dpm)]*100. Kd andKi values are calculated using GraphPad PRISM data analysis program.

[³⁵S]GTPγS Binding Assay in CHO-hμ Cell Membranes

Preparation of Membranes

CHO-hμ cell membranes are purchased from Receptor Biology, Inc.(Baltimore, Md.). About 10 mg/ml of membrane protein is suspended in 10mM TRIS-HC pH 7.2, 2 mM EDTA, 10% sucrose.

Membranes are maintained at 4-8° C. 1 ml of membranes is added into 15ml cold binding assay buffer. The assay buffer contains 50 mM HEPES, pH7.6, 5 mM MgCl₂, 100 mM NaCl, 1 mM DTT and 1 mM EDTA. The membranesuspension is homogenized with a Polytron 2 times and centrifuged at3000 rpm for 10 min. The supernatant is then centrifuged at 18,000 rpmfor 20 min. The pellet is saved in a tube and 10 ml assay buffer isadded to the tube. The pellet and buffer are mixed with a Polytron.

Incubation Procedure

The pellet membranes (20 μg/ml) are preincubated with SPA (10 mg/ml) at25 C.° for 45 min in the assay buffer. The SPA (5 mg/ml) coupled withmembranes (10 μg/ml) is then incubated with 0.5 nM [³⁵S]GTPgS in thesame HEPES buffer containing 50 μM GDP in total volume of 200 μl.Increasing concentrations of receptor agonists are used to stimulate[³⁵S]GTPgS binding. The basal binding is tested in the absence ofagonists and non-specific binding is tested in the present 10 μMunlabeled GTPγS. The data are analyzed on a Top counter.

Data% of Basal=(stimulate−non-specific)*100/(basal−non specific).% inhibition value values are calculated using a formula,% Inhibition=(% Basal of 1 uM DAMGO−% Basal of compound)*100/(% Basal of1 uM DAMGO−100)

[³⁵S]GTPγS Binding Assay in CHO-hδ Cell Membranes

Preparation of Membranes

CHO-hδ cell membranes are purchased from Receptor Biology, Inc.(Baltimore, Md.). 10 mg/ml of membrane protein is suspended in 10 mMTRIS-HC pH 7.2, 2 mM EDTA, 10% sucrose.

Membranes are maintained at 4-8° C. 1 ml of membranes is added into 15ml cold binding assay buffer. The assay buffer contained 50 mM HEPES, pH7.6, 5 mM MgCl₂, 100 mM NaCl, 1 mM DTT and 1 mM EDTA. The membranesuspension is homogenized with a Polytron 2 times and centrifuged at3000 rpm for 10 min. The supernatant is then centrifuged at 18,000 rpmfor 20 min. The pellet is saved in a tube and 10 ml assay buffer isadded into the tube. The pellet and buffer are mixed with a Polytron.

Incubation Procedure

The pellet membranes (20 μg/ml) are preincubated with SPA (10 mg/ml) at25 C.° for 45 min in the assay buffer. The SPA (5 mg/ml) coupled withmembranes (10 μg/ml) is then incubated with 0.5 nM [³⁵S]GTPgS in thesame HEPES buffer containing 50 μM GDP in total volume of 200 μl.Increasing concentrations of receptor agonists are used to stimulate[³⁵S]GTPgS binding. The basal binding is tested in the absence ofagonists and non-specific binding is tested in the presence of 10 μMunlabeled GTP S. The data are analyzed on a Top counter.

[³⁵S]GTPγS Binding Assay in NG108-15 Cell Membrane

Preparation of Membranes

NG108-15 cell membranes were purchased from Applied Cell Sciences(Rockville, Md.). An 8 mg/mL portion of membrane protein was suspendedin 10 mM TRIS-HC pH 7.2, 2 mM EDTA, 10% sucrose.

Membranes were maintained at 4-8° C. A 1 mL portion of membranes wasadded into 10 mL cold binding assay buffer. The assay buffer contained50 mM Tris, pH 7.6, 5 mM MgCl₂, 100 mM NaCl, 1 mM DTT and 1 mM EGTA. Themembrane suspension was homogenized with a Polytron for 2 times andcentrifuged at 3000 rpm for 10 min. The supernatent was then centrifugedat 18,000 rpm for 20 min. The pellet was saved in a tube and 10 ml assaybuffer was added into the tube. The pellet and buffer were mixed with aPolytron.

Incubation Procedure

The pellet membranes (75 μg/ml) were preincubated with SPA (10 mg/ml) at25 C.° for 45 min in the assay buffer. The SPA (5 mg/ml) coupled withmembranes (37.5 μg/ml) was then incubated with 0.1 nM [³⁵S]GTPγS in thesame Tris buffer containing 100 μM GDP in total volume of 200 μl.Increasing concentrations of receptor agonists were used to stimulate[³⁵S]GTPγS binding. The basal binding was tested in the absent agonistsand no specific binding was tested in the present 10 μM unlabeled GTPγS.The data were analyzed on a Top counter.

Data% of Basal=(stimulate−non specific)*100/(basal−non specific).EC50 values are calculated using a Prism program.

Mouse Abdominal Irritant Test MAIT

The procedure used was that described by Collier et al. (1968), withminor modifications. Thirty minutes after the administration of testdrug, the animals received an i.p. injection of 5.5 mg/kg ofacetylcholine bromide. The mice were then placed into large glass animaljars and were continuously observed for the first occurrence of acharacteristic behavioral response (twisting and elongation of the bodywhich extends throughout the hindlimbs) within the specified observationperiod of 10 minutes. The percent of inhibition of this response wascalculated as follows:% Inhibition=100×(Number of Nonresponders)/(Number of Animals in Group)The estimated ED₅₀ value (the dose of agonist calculated to produce 50%antinociception) and the corresponding 95% fiducial intervals weredetermined using the probit analysis of Litchfield and Wilcoxon (1949).Data% of Basal=(stimulate−non-specific)*100/(basal−non-specific).EC50 value values are calculated using a Prism program.

Rat Zymosan Radiant Heat Test

Following an overnight fast, rats were acclimated to test chambers,which have warm, glass bottoms. A radiant thermal stimulus (beam oflight) was then focused on the plantar surface of each hind paw in turn,and an initial (baseline) response time to a thermal stimulus wasrecorded for each animal. The light stimulus was automatically shut offby a photoelectric relay when the foot moved or when the cut-off timewas reached (20 seconds for radiant heat @ 5 Amps). Rats were injectedwith Zymosan A (100 μL at 25 mg/mL) subcutaneously into the sub-plantartissue of the left hind paw to stimulate an acute inflammatory reaction.

Three hours later, the response time of the animal to the thermalstimulus was then evaluated and compared to the animal's baselineresponse time. It was typically shorter, and this was recorded aspercent hyperalgesia (% H). A cut-off value for % H (˜75%) was usedduring analysis to ensure that the animals were hyperalgesic. Animalswere then dosed with test drug or vehicle. At some time(s) later(typically 60 minutes), the response time of the animal to the thermalstimulus was again evaluated.

CFA Thermal Hyperalgesia

Intraplantar injection of Complete Freund's Adjuvant (CFA) in rodentsresults in a strong, long-lasting inflammatory reaction, characterizedby a chronic and pronounced hyperalgesia to both thermal and mechanicalstimuli. These effects peak between 24-72 hours following injection andcan last for from several days to a few weeks. To assess the ability ofJNJ compounds to reverse thermal hyperalgesia, male Sprague-Dawley rats(200-350 g) were given an intraplantar injection of CFA (1:1 CFA:saline,100 μL) into their left hindpaw. Following a 24-hour incubation period,response latencies on the Radiant Heat Paw Stimulator (RH) were obtainedand compared to baseline (pre-CFA) latencies. The response isautomatically registered by the RH device when the rat lifts its pawfrom the surface of the glass. Only rats that exhibited at least a 25%reduction in response latency from baseline (i.e. hyperalgesia) wereincluded in further analysis. Following the postCFA latency assessment,rats were dosed orally (2.5 mL/kg) with test compound or vehicle(hydroxypropylmethylcellulose, HPMC). Percent Reversal of hyperalgesiawas calculated for each animal as (Treatment Response−postCFAResponse)/(preCFA Response−postCFA Response)×100. Therefore, a return tonormal pre-CFA thresholds was defined as 100% efficacy, whereas nochange from post-CFA thresholds was 0% efficacy. Average % Reversal ofhyperalgesia was then calculated for each treatment group (n=6-8rats/group). Dose response curves were subsequently obtained at the timeof peak effect. ED₅₀ values and associated statistics were calculatedusing PharmTools Plus software (The McCary Group).

Biological and Mass Spectral Data

TABLE 2 DOR hDOR hMOR GTPγS MAIT Parent Cmpd rDOR Ki rMOR Ki GTPγS GTPγS% I EC₅₀ % I @ Peak MS No. (nM) (nM) EC₅₀(nM) @10 μM (nM) 150 μmol obscalcd 1 25.5 6410 >10,000 30.8 391.28 390.230 2 0.91 2630 58.6 100377.24 376.215 3 0.95 6790 47.0 1.00 50 363.22 362.199 4 0.39 301 5529.00 7.1 511.34 510.252 5 25.3 1290 >10,000 40 481.35 480.278 6 4.257914.5 128 73.3 417.33 416.246 7 25.7 9190 1.400 1.00 76.9 377.26376.215 8 2.1 2820 620 1.00 63.6 403.28 402.231 9 >100000 >100000 363.00362.199 10 >100000 92530 523.0 522.088 11 317.35 5659 349.0 348.184 12271.25 1805.5 417.1 416.246 13 143.35 1902.5 445.1 444.187 14 432.454822.5 403.1 402.231 15 2043.5 4753 403.1 402.231 16 60.93 1145.5 440.1439.226 17 218.5 2477 429.1 428.221 18 1997 2421.5 485.1 484.236 19368.25 2873.5 389.1 388.215 20 23335 247.7 453.2 452.246 22 45.42130.0 >10,000 2.00 467.33 466.262 23 48.38 5555.5 245 403.2 402.231 240.57 5692.5 10.2 1.00 389.3 388.215 25 0.01 879.4 1.39 74.00 30(@30)469.0 468.241 26 5479 15.62 41.00 479.1 478.262 27 209 189 465.1 464.24628 0.07 811 70.3 24.00 40 443.1 442.226 29 0.05 362 31.6 34.00 30 454.5453.242 30 10.89 912 2,480 24.00 469.2 468.241 31 29.8 564 253 14.00405.1 404.221 32 72.99 1493.75 335.4 334.168 33 16.53 5423.75 401.4400.215 34 >10000 >10000 420.3 419.221 35 7.01 >10000 271 17.00 407.0406.226 36 0.79 >10000 42.5 14.00 466.3 465.242 37 2.02 >10000 921 5.00406.9 406.171 38 31.82 5518 342 429.0 428.246 39 8.43 1682.5 94.9 447.4446.257 40 11.98 >10000 267 463.8 462.234 41 5198.15 >10000 435.0433.236 42 14.67 8792 266 4.00 364.9 364.22 43 10000 >10000 379.2378.231 44 0.15 77.17 0.873 28.00 480.3 479.13 45 4.57 >100.00 14.3433.4 432.57 46 0.88 >100.00 4.79 468.60 468.60 47 4.5 48.30 125 59.23539.4 538.71 48 0.90 >100.00 18.8 66.7 405.4 404.58 49 25.0 >100.00 252459.7 458.67 50 10.2 >100.00 236 493.5 492.75 51 4.85 >100.00 62.8 449.2448.63 52 0.61 >100.00 4.44 66 50 389.3 388.22 53 50.09 >100.00 257 205960 389.3 388.22 54 68.45 715 20 361.2 360.46 55 66.48 1855 >1000 20361.2 360.46 56 161.375 711.95 40 361.2 360.46 57 396.67 5262 361.3360.46 58 1160.2 2978 375.3 374.48 59 10.56 3336.5 403 402.54 60 4.621835.8 416.9 416.57 61 133.3 7180 188 40 404.9 404.58 62 2.958 739.1 8.3533.3 404.9 404.58 63 107.5 1729 375.2 374.48 64 117.635 711.4 347.1346.43 65 197.345 857.7 333.1 332.40 66 3.1205 2954 403.2 402.54 6754.39 10887 403.2 402.54 68 0.740 1294 22 419.1 418.54 69 4.99 5830 126407.1 406.50 70 2.31 5742.5 419.1 418.54 71 5.43 2771.5 468.9 468.60Enant. A 72 0.170 375.03 468.9 468.60 Enant. B 73 11.98 884 77.9 403.4402.54 74 3.79 848.15 485.0 484.67 75 0.122 200.34 485.0 484.67 76 1.70284.5 5.91 405.1 404.51 77 1023 >10000 419.1 418.54 78 473 472.53 79473.1 472.53 80 259.65 472.6 377.3 376.52 81 77.565 837.65 377.4 376.5282 44.4 3098 405.0 404.51 83 138.56 17720 467 467.41 84 2890 37790 465.2464.61 85 3004.5 10700 466.1 465.60 86 1755 12525 455.1 454.57 87 1206029025 421.1 520.70 88 1082.5 15250 554.2 553.70 89 1953 18670 466.2465.60 90 836.15 12360 471.1 470.64 91 1351.5 6702 484.1 483.61 922.0925 2.093 55.3 389.2 388.51 93 >10000 >10000 454.4 453.59 94 2.279674.2 14.1 467 467.41 95 25.45 6516.5 465.3 464.61 96 1.692 4224 35.3466.1 465.60 97 1.7785 1806 13.3 455.1 454.57 98 24.54 7355 516.2 515.6699 19.335 3488 12.5 471.0 470.64 100 0.27385 5.854 0.452 405.0 404.51101 9.14235 532.3 19.3 466 465.60 102 68.03 2860 407.1 406.50 rDOR Ki:Rat brain delta opioid receptor binding rMOR Ki: Rat brain mu opioidreceptor binding hDOR gtp: human delta opioid receptor GTPγS functionalassay hMOR gtp: human mu opioid receptor GTPγS functional assay DOR gtp:delta opioid receptor GTPγS functional assay MAIT: Mouse AbdominalIrritant Test

Compounds 1 and 5, at 10 uM, did not significantly stimulate GTPbinding. However, at 10 uM they inhibited GTP binding induced with 1 uMDPDPE by 61% and 19%, respectively. The results indicate that these twocompounds may be delta opioid receptor antagonists.

1. A compound of Formula (I):

wherein: R₁ and R₂ are substituents independently selected from thegroup consisting of hydrogen and C₁₋₈alkanyl; R₃ is selected from thegroup consisting of hydrogen, C₁₋₈alkanyl, halo₁₋₃(C₁₋₈)alkanyl,C₂₋₈alkenyl, C₂₋₈alkynyl, C₃₋₈cycloalkanyl, cycloalkanyl(C₁₋₈)alkanyl,C₁₋₈alkanyloxy(C₁₋₈)alkanyl, C₁₋₈alkanylthio(C₁₋₈)alkanyl,hydroxyC₁₋₈alkanyl, C₁₋₈alkanyloxycarbonyl,halo₁₋₃(C₁₋₈)alkanylcarbonyl, formyl, thioformyl, carbamimidoyl,phenylimino(C₁₋₈)alkanyl, phenyl(C₁₋₈)alkanyl, phenyl(C₁₋₈)alkenyl,phenyl(C₁₋₈)alkynyl, naphthyl(C₁₋₈)alkanyl and heteroaryl(C₁₋₈)alkanyl;wherein phenyl, naphthyl and heteroaryl are optionally substituted withone to three substituents independently selected from the groupconsisting of C₁₋₆alkanyl, C₂₋₆alkenyl, C₁₋₆alkanyloxy, amino,C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino, C₁₋₆alkanylcarbonyl,C₁₋₆alkanylcarbonyloxy, C₁₋₆alkanylcarbonylamino, C₁₋₆alkanylthio,C₁₋₆alkanylsulfonyl, halogen, hydroxy, cyano, fluoroalkanyl, thioureido,and fluoroalkanyloxy; or optionally, when phenyl and heteroaryl areoptionally substituted with two substituents attached to adjacent carbonatoms, the two substituents together form a single fused moiety; whereinthe fused moiety is selected from the group consisting of —(CH₂)₃₋₅— and—O(CH₂)₁₋₃O—; R₄ is one to three substituents independently selectedfrom the group consisting of hydrogen, C₁₋₆alkanyl, C₂₋₆alkenyl,C₁₋₆alkanyloxy, amino, C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino,C₁₋₆alkanylcarbonyl, C₁₋₆alkanylcarbonyloxy, C₁₋₆alkanyloxycarbonyl,C₁₋₆alkanylaminocarbonyl, di(C₁₋₆alkanyl)aminocarbonyl,C₁₋₆alkanylcarbonylamino, C₁₋₆alkanylthio, C₁₋₆alkanylsulfonyl, halogen,hydroxy, cyano, hydroxycarbonyl, C₆₋₁₀aryl, chromanyl, chromenyl,furanyl, imidazolyl, indazolyl, indolyl, indolinyl, isoindolinyl,isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl,quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrazolyl,thiazolyl, thiophenyl, fluoroalkanyl and fluoroalkanyloxy; oroptionally, when R₄ is two substituents attached to adjacent carbonatoms, the two substituents together form a single fused moiety; whereinthe fused moiety is selected from the group consisting of —(CH₂)₃₋₅— and—O(CH₂)₁₋₃O—; R₅ is one to two substituents independently selected fromthe group consisting of hydrogen, C₁₋₆alkanyl, C₂₋₆alkenyl,C₁₋₆alkanyloxy, amino, C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino,C₁₋₆alkanylcarbonyl, C₁₋₆alkanylcarbonyloxy, C₁₋₆alkanyloxycarbonyl,C₁₋₆alkanylaminocarbonyl, C₁₋₆alkanylcarbonylamino, C₁₋₆alkanylthio,C₁₋₆alkanylsulfonyl, halogen, hydroxy, cyano, fluoroalkanyl andfluoroalkanyloxy; A is —(CH₂)_(m)—, wherein m is 0; Y is S; Z is O; andenantiomers, diastereomers, tautomers, and pharmaceutically acceptablesalts thereof.
 2. The compound according to claim 1 wherein R₁ and R₂are substituents independently selected from the group consisting ofhydrogen and C₁₋₄alkanyl.
 3. The compound according to claim 1 whereinR₁ and R₂ are substituents independently selected from the groupconsisting of hydrogen, methyl, ethyl and propyl.
 4. The compoundaccording to claim 1 wherein R₁ and R₂ are substituents independentlyselected from the group consisting of hydrogen and ethyl.
 5. Thecompound according to claim 1 wherein R₃ is selected from the groupconsisting of hydrogen, C₁₋₈alkanyl, C₂₋₈alkenyl, C₂₋₈alkynyl,C₁₋₈alkanyloxy(C₁₋₈)alkanyl, C₁₋₈alkanylthio(C₁₋₈)alkanyl,hydroxyC₁₋₈alkanyl, thioformyl, phenylimino(C₁₋₈)alkanyl,phenyl(C₁₋₈)alkanyl, and heteroaryl(C₁₋₈)alkanyl; wherein phenyl andheteroaryl are optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₆alkanyloxy andhydroxy; or optionally, when phenyl and heteroaryl are optionallysubstituted with two substituents attached to adjacent carbon atoms, thetwo substituents together form a single fused moiety; wherein the moietyis selected from O(CH₂)₁₋₃O.
 6. The compound according to claim 1wherein R₃ is selected from the group consisting of hydrogen, methyl,allyl, 2-methyl-allyl, propynyl, hydroxyethyl, thioformyl,phenyliminomethyl, phenethyl, and heteroaryl(C₁₋₈)alkanyl; wherein thephenyl in any phenyl-containing substituent is optionally substitutedwith one hydroxyl group.
 7. The compound according to claim 1 wherein R₃is hydrogen or methyl, allyl, heteroarylmethyl.
 8. The compoundaccording to claim 1 wherein R₄ is one to three substituentsindependently selected from the group consisting of hydrogen,C₁₋₆alkanyl, C₁₋₆alkanyloxy, C₁₋₆alkanylaminocarbonyl,C₁₋₆alkanylcarbonylamino, halogen, 4ydroxyl, C₆₋₁₀aryl, chromanyl,chromenyl, furanyl, imidazolyl, indazolyl, indolyl, indolinyl,isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl,oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl,pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl,tetrazolyl, thiazolyl, and thiophenyl.
 9. The compound according toclaim 1 wherein R₄ is one to two substituents independently selectedfrom the group consisting of hydrogen, C₁₋₄alkanyl, C₁₋₄alkanyloxy,halogen, phenyl, furanyl, imidazolyl, indazolyl, indolyl, indolinyl,isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl,quinolinyl, tetrazolyl, thiazolyl, thiophenyl, and hydroxyl.
 10. Thecompound according to claim 1 wherein R₄ is one to two substituentsindependently selected from the group consisting of hydrogen, methyl,methoxy, bromo, fluoro, 5- or 6-phenyl, 5- or 6-pyridinyl, 5- or6-furanyl, and hydroxyl.
 11. The compound according to claim 1 whereinR₅ is one to two substituents independently selected from the groupconsisting of hydrogen and halogen.
 12. The compound according to claim1 wherein R₅ is hydrogen.
 13. A compound of Formula (I):

wherein R₁ is C₁₋₃alkanyl; R₂ is C₁₋₃alkanyl or hydrogen; R₃ is selectedfrom the group consisting of hydrogen, C₁₋₈alkanyl, C₂₋₈alkenyl,C₂₋₈alkynyl, C₁₋₈alkanyloxy(C₁₋₈)alkanyl, C₁₋₈alkanylthio(C₁₋₈)alkanyl,hydroxyC₁₋₈alkanyl, thioformyl, phenylimino(C₁₋₈)alkanyl,phenyl(C₁₋₈)alkanyl, and heteroaryl(C₁₋₈)alkanyl; wherein phenyl andheteroaryl are optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₆alkanyloxy and5ydroxyl; or optionally, when phenyl and heteroaryl are optionallysubstituted with two substituents attached to adjacent carbon atoms, thetwo substituents together form a single fused moiety; wherein the moietyis selected from —O(CH₂)₁₋₃O—; R₄ is one to three substituentsindependently selected from the group consisting of hydrogen,C₁₋₆alkanyl, C₁₋₆alkanyloxy, C₁₋₆alkanylaminocarbonyl,C₁₋₆alkanylcarbonylamino, halogen, 5ydroxyl, C₆₋₁₀aryl, chromanyl,chromenyl, furanyl, imidazolyl, indazolyl, indolyl, indolinyl,isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl,oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl,pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl,tetrazolyl, thiazolyl, and thiophenyl; R₅ is one to two substituentsindependently selected from the group consisting of hydrogen andhalogen; A is absent; Y is S; Z is O; and enantiomers, diastereomers,tautomers, and pharmaceutically acceptable salts thereof.
 14. Thecompound according to claim 13 wherein R₁ is ethyl; R₂ is ethyl orhydrogen; and R₃ is benzo[1,3]dioxol-5-ylmethyl, carbamimidoyl,1-H-imidazol-4-yl methyl, phenyliminomethyl, 1-prop-2-ynyl, thioformyl,2-hydroxyphenyl-methyl, hydroxyethyl, methoxyethyl, 2-methyl-allyl,2-methyl-but-2-enyl, allyl, furan-3-yl methyl, H, Me, methylthioethyl,phenethyl, 6yridine-2-ylmethyl, or thiophen-2-ylmethyl.
 15. The compoundaccording to claim 13 wherein R₁ is ethyl; R₂ is ethyl; and R₃ isbenzo[1,3]dioxol-5-ylmethyl, carbamimidoyl, 1-H-imidazol-4-ylmethyl,phenyliminomethyl, 1-prop-2-ynyl, thioformyl, 2-hydroxyphenyl-methyl,hydroxyethyl, methoxyethyl, allyl, furan-3-ylmethyl, H, Me,methylthioethyl, or phenethyl.
 16. The compound according to claim 13wherein R₁ is ethyl; R₂ is ethyl; and R₃ is H,benzo[1,3]dioxol-5-ylmethyl, 1-H-imidazol-4-ylmethyl, furan-3-ylmethyl,6yridine-2-ylmethyl, or phenyliminomethyl.
 17. The compound according toclaim 13 wherein R₃ is hydrogen, methyl, allyl, or heteroarylmethyl. 18.The compound according to claim 13 wherein R₃ is hydrogen, methyl,allyl, or heteroarylmethyl; and R₄ is one to two substituentsindependently selected from the group consisting of hydrogen, methyl,methoxy, bromo, fluoro, 5- or 6-phenyl, 5- or 6-pyridinyl, 5- or6-furanyl, and hydroxy; and R₅ is hydrogen.
 19. A pharmaceuticalcomposition comprising a compound or salt according to claim 1 admixedwith a pharmaceutically acceptable carrier, excipient or diluent.
 20. Aveterinary composition comprising a compound, salt or solvate accordingto claim 1 admixed with a veterinarily acceptable carrier, excipient ordiluent.
 21. A pharmaceutical composition comprising a compound, salt orsolvate according to claim 13 admixed with a pharmaceutically acceptablecarrier, excipient or diluent.
 22. A veterinary composition comprising acompound or salt according to claim 13 admixed with a veterinarilyacceptable carrier, excipient or diluent.